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WO2022015115A1 - Utilisation thérapeutique d'une combinaison contenant un conjugué à action prolongée triplement agoniste ou un triple agoniste - Google Patents

Utilisation thérapeutique d'une combinaison contenant un conjugué à action prolongée triplement agoniste ou un triple agoniste Download PDF

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Publication number
WO2022015115A1
WO2022015115A1 PCT/KR2021/009210 KR2021009210W WO2022015115A1 WO 2022015115 A1 WO2022015115 A1 WO 2022015115A1 KR 2021009210 W KR2021009210 W KR 2021009210W WO 2022015115 A1 WO2022015115 A1 WO 2022015115A1
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Prior art keywords
cysteine
glutamine
triple
pharmaceutical composition
lysine
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PCT/KR2021/009210
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English (en)
Korean (ko)
Inventor
김정국
이종석
이상현
오의림
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hanmi Pharmaceutical Co Ltd
Hanmi Pharmaceutical Industries Co Ltd
Original Assignee
Hanmi Pharmaceutical Co Ltd
Hanmi Pharmaceutical Industries Co Ltd
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Application filed by Hanmi Pharmaceutical Co Ltd, Hanmi Pharmaceutical Industries Co Ltd filed Critical Hanmi Pharmaceutical Co Ltd
Priority to IL299841A priority Critical patent/IL299841A/en
Priority to CA3186199A priority patent/CA3186199A1/fr
Priority to EP21841859.8A priority patent/EP4183419A4/fr
Priority to US18/016,145 priority patent/US20230310630A1/en
Priority to CN202180062143.3A priority patent/CN116209475A/zh
Priority to JP2023503210A priority patent/JP2023535382A/ja
Priority to BR112023000585A priority patent/BR112023000585A2/pt
Priority to MX2023000699A priority patent/MX2023000699A/es
Priority to AU2021310793A priority patent/AU2021310793A1/en
Publication of WO2022015115A1 publication Critical patent/WO2022015115A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/6811—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • A61K38/1796—Receptors; Cell surface antigens; Cell surface determinants for hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/26—Glucagons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/605—Glucagons
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/72—Receptors; Cell surface antigens; Cell surface determinants for hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto

Definitions

  • the present invention provides a triple agonistic long-acting conjugate or a triple agonist; and an FXR agonist (farnesoid X receptor agonist), or to the therapeutic use of the combination further comprising an acetyla-CoA carboxylase inhibitor (ACC) in the combination.
  • FXR agonist farnesoid X receptor agonist
  • liver-related diseases include nonalcoholic fatty liver, hepatitis, liver fibrosis, cholestatic liver disease, cirrhosis, liver failure, liver cancer, and the like.
  • Inflammation of the liver may occur due to causes such as viruses, alcohol, drugs, immune abnormalities, metabolic diseases, and the like, and it is known that diseases such as liver fibrosis, cirrhosis, liver cancer and liver cancer occur as hepatitis progresses and becomes chronic.
  • hepatitis which is caused by inflammation of the liver, accounts for most of the liver diseases, and it is known that various liver diseases (liver fibrosis, cirrhosis, etc.) appear due to liver inflammation or liver inflammation as hepatitis progresses.
  • liver diseases liver fibrosis, cirrhosis, etc.
  • acute hepatitis and chronic hepatitis depending on the cause, can be divided into viral hepatitis, alcoholic hepatitis, drug hepatitis, and the like.
  • Cholestatic liver disease (cholestasis liver disease) is also assumed to be caused by an inflammatory disease.
  • nonalcoholic fatty liver disease is a type of disease that shows tissue findings similar to alcoholic hepatitis even though it is not related to alcohol intake.
  • NASH nonalcoholic fatty liver disease
  • Nonalcoholic fatty liver disease is on the rise as the obesity and diabetic populations increase.
  • TZD-type drugs are not applicable to patients with heart disease because of the disadvantages of large weight gain and slowing the flow of body fluids.
  • GLP-1 receptor agonists such as Victoza or Byetta
  • the drug was expected to have a therapeutic effect on nonalcoholic fatty liver disease and fibrosis caused by it in the early stage of development because it is accompanied by a weight loss effect.
  • the half-life in the body is extremely short, and since repeated administration is required every day or twice a day, there is a disadvantage in patient convenience. Such frequent administration causes great pain and discomfort to the patient.
  • GLP-1 Glucagon-like peptide-1
  • GIP Glucose-dependent insuliontropic polypeptide
  • GLP-1 has potential as a therapeutic agent for obesity, and GIP functions to promote insulin secretion from the pancreas and to lower blood sugar concentration dependent on blood sugar concentration, and increases the activity of GLP-1, anti-inflammatory effects, etc.
  • Glucagon is produced by the pancreas when blood sugar begins to drop due to a cause, such as medication or disease, or a hormone or enzyme deficiency. Glucagon signals the liver to break down glycogen to release glucose, and plays a role in raising blood sugar levels to normal levels.
  • glucagon exhibits anti-obesity effects by promoting lipolysis and energy expenditure by activating hormone-sensitive lipase in adipocytes and suppressing appetite in animals and humans, in addition to raising blood sugar. This has been reported
  • FXR agonists are FXR agonists, which are nuclear receptors activated by bile acids, also known as bile acid receptors (BARs). FXR is expressed in major sites of bile acid metabolism such as liver, intestine and kidney, and it has been reported that it acts in a tissue-specific manner to affect several metabolic pathways including bile acids as well as fibrosis. Accordingly, there is a need for an effective treatment method for liver disease mediated by FXR.
  • ACC inhibitors are known as substances that inhibit acetyla-CoA carboxylase, an enzyme important in the regulation of fatty acid production and metabolism.
  • One object of the present invention is to treat or prevent liver disease containing a pharmaceutically effective amount of a triple agonistic long-acting conjugate or a triple agonist and a pharmaceutically acceptable excipient.
  • Another object of the present invention is (i) a substance having activity on glucagon receptor, GLP-1 (Glucagon-like peptide-1) receptor, and GIP (glucose-dependent insuliontropic polypeptide) receptor, or a long-acting conjugate thereof, and (ii) a farnesoid X receptor agonist (FXR agonist).
  • Another object of the present invention is (i) a substance having activity on a glucagon receptor, a GLP-1 receptor, and a GIP receptor or a long-acting conjugate thereof, (ii) an FXR agonist, and (iii) an acetyl coenzyme A carboxylase To provide a combination comprising an inhibitor (acetyla-CoA carboxylase inhibitor, ACC inhibitor).
  • Another object of the present invention is to provide a pharmaceutical composition for preventing or treating liver disease, comprising the combination.
  • Another object of the present invention comprises (i) a substance having activity on glucagon receptor, GLP-1 receptor, and GIP receptor or a long-acting conjugate thereof, and (ii) FXR agonist (farnesoid X receptor agonist), To provide a pharmaceutical kit for the prevention or treatment of liver disease.
  • Another object of the present invention is comprising (i) a substance having activity on glucagon receptor, GLP-1 receptor, and GIP receptor or a long-acting conjugate thereof, (ii) an FXR agonist, and (iii) an ACC inhibitor, To provide a pharmaceutical kit for the prevention or treatment of liver disease.
  • Another object of the present invention is to treat liver disease comprising administering and/or using the combination, a pharmaceutical composition for the treatment or prevention of liver disease, or the pharmaceutical kit to an individual in need thereof. To provide a method of prevention or treatment.
  • Another object of the present invention is to provide use of the combination, pharmaceutical composition, or pharmaceutical kit for the prophylaxis or treatment of liver disease and/or use for the preparation of a medicament for the prevention or treatment of non-alcoholic fatty liver disease. will be.
  • the triple acting long-acting conjugate or triple agent according to the present invention and concomitant administration of an FXR agonist, or a triple acting long-acting conjugate or a triple agent; FXR agonists; And the triple combination administration regimen of an ACC inhibitor has an improved effect compared to a single administration regimen, so it can be usefully used for the prevention or treatment of liver disease.
  • FIG. 1 is a diagram showing the change in NAS (NAFLD activity score) according to the complex administration of the long-acting conjugate of the triple activator (*p ⁇ 0.05, **p ⁇ 0.01, ***p ⁇ 0.001 vs. CH-HFD , vehicle control by ono-way ANOVA).
  • FIG. 2 is a diagram showing the change in the content of hydroxyprolin in liver tissue according to the complex administration of the long-acting conjugate of the triple activator (*p ⁇ 0.05, **p ⁇ 0.01, ***p ⁇ 0.001 vs. CH-HFD, vehicle control by ono-way ANOVA).
  • One aspect embodying the present invention is a pharmaceutical composition for the treatment or prevention of liver disease comprising a triple agonistic long-acting conjugate or a triple agonist, the pharmaceutical composition
  • the red composition is a composition characterized in that it is used in combination with a farnesoid X receptor agonist.
  • the pharmaceutical composition contains a pharmaceutically effective amount of a triple-acting long-acting conjugate or a triple agonist and a pharmaceutically acceptable excipient for the treatment or prevention of liver disease.
  • a composition a pharmaceutically effective amount of a triple-acting long-acting conjugate or a triple agonist and a pharmaceutically acceptable excipient for the treatment or prevention of liver disease.
  • the pharmaceutical composition is characterized in that it is used in combination with a farnesoid X receptor agonist,
  • the triple-acting long-acting conjugate is characterized in that the pharmaceutical composition is a substance represented by the following formula (1):
  • Lx is a linker containing an ethylene glycol repeating unit, and x is 0 or a natural number
  • Fc is an immunoglobulin Fc region
  • Z or triple agent is a peptide comprising an amino acid sequence represented by the following general formula 1,
  • Xaa1 is histidine (His, H), 4-imidazoacetyl (CA) or tyrosine (Tyr, Y),
  • Xaa2 is glycine (Gly, G), alpha-methyl-glutamic acid or 2-aminoisobutyric acid (Aib),
  • Xaa3 is glutamic acid (Glu, E) or glutamine (Gln, Q),
  • Xaa7 is threonine (Thr, T) or isoleucine (Ile, I),
  • Xaa10 is leucine (Leu, L), tyrosine (Tyr, Y), lysine (Lys, K), cysteine (Cys, C) or valine (Val, V);
  • Xaa12 is lysine (Lys, K), serine (Ser, S) or isoleucine (Ile, I);
  • Xaa13 is glutamine (Gln, Q), tyrosine (Tyr, Y), alanine (Ala, A) or cysteine (Cys, C);
  • Xaa14 is leucine (Leu, L), methionine (Met, M) or tyrosine (Tyr, Y);
  • Xaa15 is cysteine (Cys, C), aspartic acid (Asp, D), glutamic acid (Glu, E) or leucine (Leu, L),
  • Xaa16 is glycine (Gly, G), glutamic acid (Glu, E) or serine (Ser, S);
  • Xaa17 is glutamine (Gln, Q), arginine (Arg, R), isoleucine (Ile, I), glutamic acid (Glu, E), cysteine (Cys, C) or lysine (Lys, K);
  • Xaa18 is alanine (Ala, A), glutamine (Gln, Q), arginine (Arg, R) or histidine (His, H);
  • Xaa19 is alanine (Ala, A), glutamine (Gln, Q), cysteine (Cys, C) or valine (Val, V);
  • Xaa20 is lysine (Lys, K), glutamine (Gln, Q) or arginine (Arg, R);
  • Xaa21 is glutamic acid (Glu, E), glutamine (Gln, Q), leucine (Leu, L), cysteine (Cys, C) or aspartic acid (Asp, D);
  • Xaa23 is isoleucine (Ile, I) or valine (Val, V),
  • Xaa24 is alanine (Ala, A), glutamine (Gln, Q), cysteine (Cys, C), asparagine (Asn, N), aspartic acid (Asp, D) or glutamic acid (Glu, E),
  • Xaa27 is valine (Val, V), leucine (Leu, L) or lysine (Lys, K);
  • Xaa28 is cysteine (Cys, C), lysine (Lys, K), alanine (Ala, A), asparagine (Asn, N) or aspartic acid (Asp, D);
  • Xaa29 is cysteine (Cys, C), glycine (Gly, G), glutamine (Gln, Q), threonine (Thr, T), glutamic acid (Glu, E) or histidine (His, H);
  • Xaa30 is cysteine (Cys, C), glycine (Gly, G), lysine (Lys, K) or histidine (His, H), or is absent;
  • R1 is cysteine (Cys, C), GKKNDWKHNIT (SEQ ID NO: 106), m-SSGAPPPS-n (SEQ ID NO: 107) or m-SSGQPPPS-n (SEQ ID NO: 108), or is absent;
  • m is -Cys-, -Pro- or -Gly-Pro-;
  • n is absent or is -Cys-, -Gly-, -Ser- or -His-Gly-.
  • Xaa2 is glycine, alpha-methyl-glutamic acid or 2-aminoisobutyric acid,
  • Xaa7 is threonine
  • Xaa10 is tyrosine, cysteine or valine
  • Xaa12 is lysine or isoleucine
  • Xaa13 is tyrosine, alanine, glutamine or cysteine,
  • Xaa14 is leucine, tyrosine or methionine
  • Xaa15 is cysteine, leucine, glutamic acid or aspartic acid,
  • Xaa17 is glutamine, arginine, isoleucine, cysteine, glutamic acid or lysine,
  • Xaa18 is alanine, glutamine, arginine or histidine;
  • Xaa19 is alanine, glutamine, valine or cysteine
  • Xaa20 is lysine, arginine or glutamine
  • Xaa21 is glutamic acid, glutamine, leucine, cysteine or aspartic acid,
  • Xaa23 is isoleucine or valine
  • Xaa24 is cysteine, alanine, glutamine, asparagine, glutamic acid or aspartic acid;
  • Xaa27 is characterized in that it is leucine or lysine.
  • composition according to any one of the preceding embodiments, wherein the Z or triple agent is a peptide comprising an amino acid sequence represented by the following general formula 2:
  • Xaa1 is 4-imidazoacetyl, histidine or tyrosine;
  • Xaa2 is glycine, alpha-methyl-glutamic acid or 2-aminoisobutyric acid;
  • Xaa10 is tyrosine or cysteine
  • Xaa13 is alanine, glutamine, tyrosine or cysteine,
  • Xaa14 is leucine, methionine or tyrosine
  • Xaa15 is aspartic acid, glutamic acid or leucine
  • Xaa16 is glycine, glutamic acid or serine,
  • Xaa17 is glutamine, arginine, isoleucine, glutamic acid, cysteine or lysine,
  • Xaa18 is alanine, glutamine, arginine or histidine;
  • Xaa19 is alanine, glutamine, cysteine or valine
  • Xaa20 is lysine, glutamine or arginine
  • Xaa21 is cysteine, glutamic acid, glutamine, leucine or aspartic acid,
  • Xaa23 is isoleucine or valine
  • Xaa24 is cysteine, alanine, glutamine, asparagine or glutamic acid,
  • Xaa28 is lysine, cysteine, asparagine or aspartic acid
  • Xaa29 is glycine, glutamine, cysteine or histidine
  • Xaa30 is cysteine, glycine, lysine or histidine
  • Xaa31 is proline or cysteine
  • Xaa40 is cysteine or absent.
  • composition according to any one of the preceding embodiments, wherein the Z or triple agent is a peptide comprising an amino acid sequence represented by the following general formula 3:
  • Xaa1 is histidine or tyrosine
  • Xaa2 is alpha-methyl-glutamic acid or 2-aminoisobutyric acid
  • Xaa13 is alanine, tyrosine or cysteine
  • Xaa17 is arginine, cysteine or lysine
  • Xaa18 is alanine or arginine
  • Xaa19 is alanine or cysteine
  • Xaa21 is glutamic acid or aspartic acid
  • Xaa24 is glutamine or asparagine
  • Xaa28 is cysteine or aspartic acid
  • Xaa29 is cysteine, histidine or glutamine
  • Xaa30 is cysteine or histidine
  • Xaa31 is proline or cysteine
  • Xaa40 is cysteine or absent.
  • Xaa16 is glutamic acid
  • Xaa20 is lysine
  • the glutamic acid and the lysine form a lactam ring.
  • composition according to any one of the preceding embodiments, wherein the Z or triple agent is amidated at its C-terminus.
  • composition according to any one of the preceding embodiments, wherein the formula weight of the ethylene glycol repeating unit moiety in Lx is in the range of 1 to 100 kDa.
  • composition according to any one of the preceding embodiments, wherein the Z or triple agent is a peptide comprising one amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 102.
  • composition according to any one of the preceding embodiments, wherein the Z or triple agent is SEQ ID NO: 21, 22, 42, 43, 50, 64, 66, 67, 70, 71, 76, 77, 96, 97 and It is characterized in that it is a peptide comprising an amino acid sequence selected from the group consisting of 100.
  • composition according to any one of the preceding embodiments, wherein the Z or triple agent is an amino acid selected from the group consisting of SEQ ID NOs: 21, 22, 42, 43, 50, 66, 67, 77, 96, 97 and 100 It is characterized in that it is a peptide comprising a sequence.
  • composition according to any one of the preceding embodiments, wherein the Z or triple agent is a peptide comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 21, 22, 42, 43, 50, 77 and 96 do it with
  • the farnesoid X receptor agonist is cafestol (Cafestol), chenodeoxycholic acid, obeticholic acid, fexaramine ( Fexaramine), GW 4064, PX104, 6E-CDCA (6-ethyl-chedeoxycholic acid), AKN-083, Tropifexor, Cilofexor, EDP-305, AGN-242266, AGN-242256, EP- 024297, RDX-023, BWL-200, GNF-5120, GS-9674, LMB-763, Px-102, Px-103, M790, M780, M450, M-480, MET-409, MET-642, PX20606, It is characterized in that at least one selected from the group consisting of EYP-001, TERN-101, TC-100 and INT-2228.
  • composition according to any one of the preceding embodiments, wherein the pharmaceutical composition is also used in combination with an acetyl-Coenzyme A carboxylase inhibitor.
  • acetyl coenzyme A carboxylase inhibitor is CP-640186, (4-piperidinyl)-piperazine derivatives ((4-piperidinyl)-piperazine derivatives), 1, 4-substituted cyclohexane derivatives, spirochromanone derivatives, spirolactam derivatives, spirodiamine derivatives, spiropentacylamide derivatives , Pseudopeptide pyrrolidinedione derivatives, Macrocyclic polyketone derivatives, Thiophene pyrimidone derivatives including firsocostat, amino-oxazole It is characterized in that at least one selected from the group consisting of amino-oxazole derivatives, azobenzimidazole derivatives and PF-05221304.
  • liver disease is non-alcoholic fatty liver disease or cholestatic liver disease.
  • nonalcoholic fatty liver disease is at least selected from the group consisting of steatosis simplex, liver inflammation, nonalcoholic fatty liver, nonalcoholic steatohepatitis, cirrhosis, liver fibrosis, liver failure, and liver cancer. It is characterized as a single disease.
  • composition according to any one of the preceding embodiments, wherein the cholestatic liver disease is any one selected from the group consisting of primary biliary cirrhosis, primary sclerosing cholangitis, and combinations thereof. characterized in that
  • nonalcoholic fatty liver disease is at least one disease selected from the group consisting of liver inflammation, nonalcoholic steatohepatitis and liver fibrosis.
  • Another aspect embodying the present invention is (i) a substance having activity against glucagon receptors, GLP-1 (Glucagon-like peptide-1) receptors, and GIP (Glucose-dependent insuliontropic polypeptide) receptors or long-acting conjugates thereof , and (ii) a farnesoid X receptor agonist.
  • the combination further comprises (iii) an acetyla-CoA carboxylase inhibitor.
  • the substance having activity on the glucagon receptor, the GLP-1 receptor, and the GIP receptor is a peptide comprising the amino acid sequence represented by the general formula 1 described above. do.
  • Xaa14 is leucine or methionine
  • Xaa15 is characterized in that it is cysteine, aspartic acid, or leucine.
  • Xaa2 is glycine, alpha-methyl-glutamic acid, or Aib;
  • Xaa7 is threonine
  • Xaa10 is tyrosine, cysteine, or valine
  • Xaa12 is lysine or isoleucine
  • Xaa13 is tyrosine, alanine, or cysteine
  • Xaa14 is leucine or methionine
  • Xaa15 is cysteine or aspartic acid
  • Xaa17 is glutamine, arginine, isoleucine, cysteine, or lysine;
  • Xaa18 is alanine, arginine, or histidine
  • Xaa19 is alanine, glutamine, or cysteine
  • Xaa20 is lysine or glutamine
  • Xaa21 is glutamic acid, cysteine, or aspartic acid
  • Xaa23 is valine
  • Xaa24 is alanine, glutamine, cysteine, asparagine, or aspartic acid
  • Xaa27 is characterized in that it is leucine or lysine.
  • Xaa13 is alanine, tyrosine, or cysteine
  • Xaa15 is aspartic acid or glutamic acid
  • Xaa17 is glutamine, arginine, cysteine, or lysine
  • Xaa18 is alanine, arginine, or histidine
  • Xaa21 is cysteine, glutamic acid, glutamine, or aspartic acid
  • Xaa23 is isoleucine or valine
  • Xaa24 is cysteine, glutamine, or asparagine
  • Xaa28 is cysteine, asparagine, or aspartic acid
  • Xaa29 is glutamine, cysteine, or histidine
  • Xaa30 is characterized in that it is cysteine, lysine, or histidine.
  • Xaa2 is alpha-methyl-glutamic acid or Aib
  • Xaa7 is threonine
  • Xaa10 is tyrosine or cysteine
  • Xaa12 is lysine or isoleucine
  • Xaa13 is tyrosine, alanine, or cysteine
  • Xaa14 is leucine or methionine
  • Xaa15 is cysteine or aspartic acid
  • Xaa16 is glutamic acid
  • Xaa17 is arginine, isoleucine, cysteine, or lysine;
  • Xaa18 is alanine, arginine, or histidine
  • Xaa19 is alanine, glutamine, or cysteine
  • Xaa20 is lysine or glutamine
  • Xaa21 is glutamic acid or aspartic acid
  • Xaa23 is valine
  • Xaa24 is glutamine, asparagine, or aspartic acid
  • Xaa27 is leucine
  • Xaa28 is characterized in that it is cysteine, alanine, asparagine, or aspartic acid.
  • Xaa1 is histidine or 4-imidazoacetyl
  • Xaa2 is alpha-methyl-glutamic acid or Aib
  • Xaa3 is glutamine
  • Xaa7 is threonine
  • Xaa10 is tyrosine
  • Xaa12 is isoleucine
  • Xaa13 is alanine or cysteine
  • Xaa14 is methionine
  • Xaa15 is aspartic acid
  • Xaa16 is glutamic acid
  • Xaa17 is isoleucine or lysine
  • Xaa18 is alanine or histidine
  • Xaa19 is glutamine or cysteine
  • Xaa20 is lysine
  • Xaa21 is aspartic acid
  • Xaa23 is valine
  • Xaa24 is asparagine
  • Xaa27 is leucine
  • Xaa28 is alanine or asparagine
  • Xaa29 is glutamine or threonine
  • Xaa30 is characterized in that it is cysteine or lysine, or is absent.
  • the substance having activity on the glucagon receptor, the GLP-1 receptor, and the GIP receptor is a peptide comprising the amino acid sequence of Formula 3 as described above.
  • R1 is cysteine, GKKNDWKHNIT (SEQ ID NO: 106), CSSGQPPPS (SEQ ID NO: 109), GPSSGAPPPS (SEQ ID NO: 110), GPSSGAPPPSC (SEQ ID NO: 111), PSSGAPPPS (SEQ ID NO: 112), PSSGAPPPSG (SEQ ID NO: 113), PSSGAPPPSHG (SEQ ID NO: 113) 114), PSSGAPPPSS (SEQ ID NO: 115), PSSGQPPPS (SEQ ID NO: 116), or PSSGQPPPSC (SEQ ID NO: 117), or is characterized in that it is absent.
  • the substance having activity on the glucagon receptor, the GLP-1 receptor, and the GIP receptor is a peptide comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 102 characterized.
  • the FXR agonist is cafestol, Chenodeoxycholic acid, Obeticholic acid, Fexaramine, GW 4064, PX104 , 6E-CDCA (6-ethyl-chedeoxycholic acid), AKN-083 and Tropifexor, Cilofexor, EDP-305 AGN-242266, AGN-242256, EP-024297, RDX-023, BWL- 200, GNF-5120, GS-9674, LMB-763, Px-102, Px-103, M790, M780, M450, M-480, MET-409, MET-642, PX20606, EYP-001, TERN-101, It is characterized in that it is selected from the group consisting of TC-100 and INT-2228.
  • the ACC inhibitor is CP-640186, (4-piperidinyl)-piperazine derivatives, 1,4-substituted cyclohexane derivatives (1,4-disubstituted cyclohexane derivatives), Spirochromanone derivatives, Spirolactam derivatives, Spirodiamine derivatives, Spiropentacylamide derivatives, Pseudopeptide pyrrolidine Ionic derivatives (Pseudopeptide pyrrolidinedione derivatives), Macrocyclic polyketone derivatives (Macrocyclic polyketone derivatives), Thiophene pyrimidone derivatives including firsocostat, Amino-oxazole derivatives ), azobenzimidazole derivatives, and PF-05221304.
  • the conjugate is a glucagon receptor, a GLP-1 receptor, and a biocompatible substance capable of increasing the in vivo half-life of a substance having activity on the GIP receptor bound, long-acting It is characterized in that it is in the form of a conjugate.
  • the substance having activity on the glucagon receptor, the GLP-1 receptor, and the GIP receptor is a peptide comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 102,
  • the conjugate thereof is characterized in that the peptide and the immunoglobulin Fc region are linked through a linker, which is a non-peptide polymer.
  • Another embodiment embodying the present invention is a pharmaceutical composition for preventing or treating liver disease, comprising the combination.
  • the liver disease is characterized in that non-alcoholic fatty liver disease (non-alcoholic fatty liver disease) or cholestatic liver disease.
  • nonalcoholic fatty liver disease is selected from the group consisting of simple steatosis, liver inflammation, nonalcoholic fatty liver, nonalcoholic steatohepatitis, cirrhosis, liver fibrosis, liver failure and liver cancer. do it with
  • composition according to any one of the preceding embodiments, wherein the cholestatic liver disease is characterized in that it is any one selected from the group consisting of primary biliary cirrhosis, primary sclerosing cholangitis, and combinations thereof.
  • glucagon receptor GLP-1 (Glucagon-like peptide-1) receptor
  • GIP glycose-dependent insuliontropic
  • Polypeptide is a pharmaceutical composition for preventing or treating liver disease, including a substance having activity on the receptor or a conjugate thereof.
  • the composition is characterized in that it is further used in combination with an ACC inhibitor (acetyla-CoA carboxylase inhibitor).
  • an ACC inhibitor acetyla-CoA carboxylase inhibitor
  • Another aspect embodying the present invention is (i) a substance having activity on a glucagon receptor, a GLP-1 receptor, and a GIP receptor, or a long-acting conjugate thereof, and (ii) an FXR agonist, the prevention of liver disease or a pharmaceutical kit for treatment.
  • the kit is characterized in that it further comprises (iii) an ACC inhibitor.
  • Another embodiment embodying the present invention is a liver comprising the step of administering and/or using the combination, a pharmaceutical composition for the treatment or prevention of liver disease, or the pharmaceutical kit to an individual in need thereof A method for preventing or treating a disease.
  • Another aspect embodying the present invention is the use of the combination, pharmaceutical composition, or pharmaceutical kit for the prophylaxis or treatment of liver disease and/or use for the manufacture of a medicament for the prophylaxis or treatment of liver disease.
  • One aspect embodying the present invention is a pharmaceutical composition for the treatment or prevention of liver disease comprising a triple agonistic long-acting conjugate or a triple agonist, wherein the pharmaceutical composition is Provided is a pharmaceutical composition characterized in that it is used in combination with a farnesoid X receptor agonist (FXR agonist).
  • FXR agonist farnesoid X receptor agonist
  • the "triple-acting long-acting conjugate” is a glucagon receptor, GLP-1 (Glucagon-like peptide-1) receptor, and GIP (Glucose-dependent insuliontropic polypeptide) having activity on the receptor, the peptide having its in vivo half-life It refers to a long-acting conjugate to which the increasing biocompatible material part is bound.
  • the biocompatible material may be mixed with a carrier.
  • the "substance (or peptide) having activity on the glucagon receptor, the GLP-1 receptor, and the GIP receptor” may be referred to as a "triple agonis, trigonal agonist” or "triple activator".
  • the "triple-acting long-acting conjugate”, which is a conjugate of the peptide, may exhibit increased durability of potency compared to the peptide to which a carrier is not bound, and in the present invention, such a conjugate is referred to as a "long-acting conjugate” and “conjugate”, “long-acting conjugate of triple activator”, or “conjugate of substances having activity against glucagon receptor, GLP-1 receptor, and GIP receptor” may be used interchangeably.
  • the pharmaceutical composition is a pharmaceutical composition for the treatment or prevention of liver disease containing a pharmaceutically effective amount of a triple-acting long-acting conjugate or a triple agent and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition is characterized in that it is used in combination with a farnesoid X receptor agonist.
  • Lx is a linker containing an ethylene glycol repeating unit, and x is 0 or a natural number
  • Fc is an immunoglobulin Fc region
  • Z or triple agent is a peptide comprising an amino acid sequence represented by the following general formula 1,
  • Xaa1 is histidine (His, H), 4-imidazoacetyl (CA) or tyrosine (Tyr, Y),
  • Xaa2 is glycine (Gly, G), alpha-methyl-glutamic acid or 2-aminoisobutyric acid (Aib),
  • Xaa3 is glutamic acid (Glu, E) or glutamine (Gln, Q),
  • Xaa7 is threonine (Thr, T) or isoleucine (Ile, I),
  • Xaa10 is leucine (Leu, L), tyrosine (Tyr, Y), lysine (Lys, K), cysteine (Cys, C) or valine (Val, V);
  • Xaa12 is lysine (Lys, K), serine (Ser, S) or isoleucine (Ile, I);
  • Xaa13 is glutamine (Gln, Q), tyrosine (Tyr, Y), alanine (Ala, A) or cysteine (Cys, C);
  • Xaa14 is leucine (Leu, L), methionine (Met, M) or tyrosine (Tyr, Y);
  • Xaa15 is cysteine (Cys, C), aspartic acid (Asp, D), glutamic acid (Glu, E) or leucine (Leu, L),
  • Xaa16 is glycine (Gly, G), glutamic acid (Glu, E) or serine (Ser, S);
  • Xaa17 is glutamine (Gln, Q), arginine (Arg, R), isoleucine (Ile, I), glutamic acid (Glu, E), cysteine (Cys, C) or lysine (Lys, K);
  • Xaa18 is alanine (Ala, A), glutamine (Gln, Q), arginine (Arg, R) or histidine (His, H);
  • Xaa19 is alanine (Ala, A), glutamine (Gln, Q), cysteine (Cys, C) or valine (Val, V);
  • Xaa20 is lysine (Lys, K), glutamine (Gln, Q) or arginine (Arg, R);
  • Xaa21 is glutamic acid (Glu, E), glutamine (Gln, Q), leucine (Leu, L), cysteine (Cys, C) or aspartic acid (Asp, D);
  • Xaa23 is isoleucine (Ile, I) or valine (Val, V),
  • Xaa24 is alanine (Ala, A), glutamine (Gln, Q), cysteine (Cys, C), asparagine (Asn, N), aspartic acid (Asp, D) or glutamic acid (Glu, E),
  • Xaa27 is valine (Val, V), leucine (Leu, L) or lysine (Lys, K);
  • Xaa28 is cysteine (Cys, C), lysine (Lys, K), alanine (Ala, A), asparagine (Asn, N) or aspartic acid (Asp, D);
  • Xaa29 is cysteine (Cys, C), glycine (Gly, G), glutamine (Gln, Q), threonine (Thr, T), glutamic acid (Glu, E) or histidine (His, H);
  • Xaa30 is cysteine (Cys, C), glycine (Gly, G), lysine (Lys, K) or histidine (His, H), or is absent;
  • R1 is cysteine (Cys, C), GKKNDWKHNIT (SEQ ID NO: 106), m-SSGAPPPS-n (SEQ ID NO: 107) or m-SSGQPPPS-n (SEQ ID NO: 108), or is absent;
  • m is -Cys-, -Pro- or -Gly-Pro-;
  • n is absent or is -Cys-, -Gly-, -Ser- or -His-Gly-.
  • Xaa27 may be exceptionally methionine (Met, M).
  • the pharmaceutical composition may be used in combination with an acetyl-Coenzyme A carboxylase inhibitor (ACC inhibitor).
  • ACC inhibitor acetyl-Coenzyme A carboxylase inhibitor
  • Another aspect of the present invention is (i) a substance having activity on glucagon receptor, GLP-1 receptor, and GIP receptor or a long-acting conjugate thereof, and (ii) FXR agonist (farnesoid X receptor agonist) in combination treatment provide academic use.
  • Another embodiment includes (i) a substance having activity on glucagon receptors, GLP-1 receptors, and GIP receptors or long-acting conjugates thereof, (ii) FXR agonists, and (iii) ACC inhibitors (acetyla-CoA carboxylase inhibitors) ) provides a therapeutic use in combination.
  • Another embodiment provides a pharmaceutical composition for preventing or treating liver disease using (i) a triple-acting long-acting conjugate or a triple agonist and (ii) an FXR agonist.
  • Another embodiment provides a pharmaceutical composition for the prophylaxis or treatment of liver disease using (i) a triple acting long-acting conjugate or triple agent, (ii) an FXR agonist, and (iii) an ACC inhibitor.
  • one aspect of the present invention relates to a substance having activity on glucagon receptors, GLP-1 receptors, and GIP receptors (triple agonist) or a long-acting conjugate thereof (triple-acting long-acting conjugate); and a combination, pharmaceutical composition, or kit comprising an FXR agonist.
  • the triple agonist or a long-acting conjugate thereof; and the combination, pharmaceutical composition, or kit comprising a FXR agonist may be a combination, pharmaceutical composition, or kit for the prophylaxis or treatment of liver disease.
  • the combination may further comprise an ACC inhibitor, in this case, a substance having activity on the glucagon receptor, the GLP-1 receptor, and the GIP receptor (triple agonist) or a conjugate thereof (triple action long-acting conjugate) ; FXR agonists; and an ACC inhibitor.
  • an ACC inhibitor in this case, a substance having activity on the glucagon receptor, the GLP-1 receptor, and the GIP receptor (triple agonist) or a conjugate thereof (triple action long-acting conjugate) ; FXR agonists; and an ACC inhibitor.
  • the combination, pharmaceutical composition, or kit comprising an ACC inhibitor may be a combination, pharmaceutical composition, or kit for the prophylaxis or treatment of liver disease.
  • the term "combination” refers to (a) a substance having activity on a glucagon receptor, a GLP-1 receptor, and a GIP receptor (triple agonist) or a long-acting conjugate thereof (triple-acting long-acting conjugate) ); and (b) an FXR agonist, or (b') an FXR agonist and an ACC inhibitor.
  • This includes, but is not limited to, a triple-acting long-acting conjugate or a pharmaceutical composition characterized in that a triple-agonist and an FXR agonist are used in combination, or a composition in which an ACC inhibitor is additionally used in combination with the pharmaceutical composition.
  • a substance having activity on the glucagon receptor, the GLP-1 receptor, and the GIP receptor (triple agonist) or a long-acting conjugate thereof (triple-acting long-acting conjugate); and (b) concomitant administration of an FXR agonist may be used interchangeably as “combined administration” or “combined administration”, wherein (a) a substance having activity on the glucagon receptor, the GLP-1 receptor, and the GIP receptor (triple agonist) ) or a conjugate thereof (triple-acting long-acting conjugate); and (b') co-administration of an FXR agonist and an ACC inhibitor may be used interchangeably as “triple combined administration” and “triple combined administration”.
  • the combination or pharmaceutical composition is
  • a) (i) a substance having activity on the glucagon receptor, the GLP-1 receptor, and the GIP receptor (triple agonist) or a long-acting conjugate thereof (triple-acting long-acting conjugate) and (ii) an FXR agonist mixed It is administered as a mixture, or (i) a substance having activity on the glucagon receptor, the GLP-1 receptor, and the GIP receptor (triple agonist) or a long-acting conjugate thereof (triple-acting long-acting type) conjugate), (ii) an FXR agonist, and (iii) an ACC inhibitor are administered in one mixture; or
  • an FXR agonist and an ACC inhibitor are in an isolated form, glucagon receptor, GLP-1 receptor , and substances having activity on the GIP receptor (triple agonist) or long-acting conjugates thereof (triple-acting long-acting conjugates) and FXR agonists; or a substance having activity on the GLP-1 receptor, and the GIP receptor (triple agonist) or a long-acting conjugate thereof (triple-acting long-acting conjugate), an FXR agonist and an ACC inhibitor are formulated in separate formulations, , sequentially
  • “concomitant administration”, “combination” and “in combination” do not only mean simultaneous administration, but also a) (i) having activity on the glucagon receptor, the GLP-1 receptor, and the GIP receptor. a substance (a triple agonist) or a long-acting conjugate thereof (a triple-acting long-acting conjugate) and (ii) an FXR agonist; or b) (i) a GLP-1 receptor, and a substance having activity on the GIP receptor (triple agonist) or a long-acting conjugate thereof (triple-acting long-acting conjugate), (ii) an FXR agonist and (iii) an ACC
  • the inhibitors act together on the subject so that each of the substances ((i), (ii) and/or (iii)) performs at a level equal to or greater than its intended function.
  • composition comprising a combination refers to a substance having activity on the glucagon receptor, the GLP-1 receptor, and the GIP receptor (triple agonist) or a long-acting conjugate thereof (triple action lasting type conjugates) and FXR agonists; or a combination comprising a GLP-1 receptor, and a substance having activity on the GIP receptor (triple agonist) or a long-acting conjugate thereof (triple-acting long-acting conjugate), an FXR agonist and an ACC inhibitor, or and may have therapeutic uses, but is not limited thereto. For example, it may have a use for preventing or treating liver disease, but is not limited thereto.
  • composition comprising a combination may be used interchangeably with “composition”.
  • substances having activity on glucagon receptors, GLP-1 receptors, and GIP receptors (triple agonists) or long-acting conjugates thereof (triple-acting long-acting conjugates) and FXR agonists;
  • the GLP-1 receptor, and a substance having activity on the GIP receptor (triple agonist) or a long-acting conjugate thereof an FXR agonist and an ACC inhibitor may be administered simultaneously, separately, sequentially, or in reverse order, but is not limited thereto does not
  • the term "kit” refers to a substance having activity on a glucagon receptor, a GLP-1 receptor, and a GIP receptor (triple agonist) or a long-acting conjugate thereof (triple-acting long-acting conjugate) and an FXR agonist; or a substance having activity on a glucagon receptor, a GLP-1 receptor, and a GIP receptor (triple agonist) or a long-acting conjugate thereof (triple-acting long-acting conjugate), an FXR agonist and an ACC inhibitor, It may be one comprising the combination or composition according to the invention.
  • the kit according to the present invention includes a substance having activity on the glucagon receptor, GLP-1 receptor, and GIP receptor formulated as one formulation (triple agonist) or a long-acting conjugate thereof (triple-acting long-acting conjugate) ) and FXR agonists; or substances having activity on glucagon receptors, GLP-1 receptors, and GIP receptors (triple agonist) or long-acting conjugates thereof (triple-acting long-acting conjugates), FXR agonists and ACC inhibitors and may additionally include a material necessary for the combined administration of two substances or three substances, but is not limited thereto.
  • the present invention relates to a substance having activity against glucagon receptors, GLP-1 receptors, and GIP receptors having a prophylactic or therapeutic effect on liver disease (triple agonist) or a long-acting conjugate thereof (triple-acting long-acting conjugate) FXR agent; Or when used in combination with an FXR agonist and an ACC inhibitor, a substance having activity on the glucagon receptor, the GLP-1 receptor, and the GIP receptor (triple agonist) or a long-acting conjugate thereof (triple-acting long-acting type) It was confirmed that the preventive or therapeutic effect of liver disease is dramatically improved compared to the conjugate) alone, and thus the combination therapy was provided.
  • the “substance having activity on the glucagon receptor, the GLP-1 receptor, and the GIP receptor” may be a “peptide having activity on the glucagon receptor, the GLP-1 receptor, and the GIP receptor”.
  • “triple agonist” or “triple active agent” may be used interchangeably.
  • the triple activator may be Z, which is a component of Formula 1 above.
  • Such peptides include various substances with significant levels of activity on glucagon, GLP-1, and GIP receptors, such as various peptides.
  • the triple activator having a significant level of activity on the glucagon, GLP-1, and GIP receptors includes one or more receptors of glucagon, GLP-1, and GIP receptors, specifically two or more More specifically, the in vitro activity for all three receptors is about 0.001% or more, about 0.01% or more, compared to the native ligand (natural glucagon, native GLP-1, and native GIP) of the corresponding receptor; about 0.1% or more, about 1% or more, about 2% or more, about 3% or more, about 4% or more, about 5% or more, about 6% or more, about 7% or more, about 8% or more, about 9% or more, about 10% or more, about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, about 100% or more, about It may represent 150% or more, about 200% or more, but a significantly increased range is included without limitation
  • the activity on the receptor is about 0.001% or more, 0.01% or more, 0.1% or more, 1% or more, 2% or more, 3% or more, 4% or more, 5% or more, the in vitro activity of the receptor compared to the native type. , 6% or more, 7% or more, 8% or more, 9% or more, 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90 % or more, 100% or more, or about 200% or more may be exemplified. However, the present invention is not limited thereto.
  • the term “about” includes all values within a range including ⁇ 0.5, ⁇ 0.4, ⁇ 0.3, ⁇ 0.2, ⁇ 0.1, etc., and includes all values in a range equal to or similar to the value following the term about, but not limited
  • Example 3 of the present specification may be referred to, but is not particularly limited thereto.
  • the peptide is characterized in that it possesses one or more, two or more, specifically three activities of the following i) to iii), specifically, it possesses a significant activity:
  • activating the receptor means that the in vitro activity of the receptor compared to the native type is about 0.001% or more, about 0.1% or more, about 1% or more, about 2% or more, about 3% or more, about 4% or more, about 5 % or more, about 6% or more, about 7% or more, about 8% or more, about 9% or more, about 10% or more, about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60 % or more, about 70% or more, about 80% or more, about 90% or more, about 100% or more, about 150% or more, about 200% or more may be exemplified. However, the present invention is not limited thereto.
  • the peptide may have an increased half-life in the body compared to any one of native GLP-1, native glucagon, and native GIP, but is not particularly limited thereto.
  • the peptide may be non-naturally occurring.
  • Such a peptide may include an intramolecular bridge (eg, a covalent bridge or a non-covalent bridge), and specifically may be in a form containing a ring, for example, at positions 16 and 20 of the peptide. It may be in the form of a ring formed between amino acids, but is not particularly limited thereto.
  • the amino acid at position 16 may be glutamic acid
  • the amino acid at position 20 may be lysine, but is not limited thereto.
  • Non-limiting examples of the ring may include a lactam bridge (or lactam ring).
  • the peptide includes all those modified to include a ring and an amino acid capable of forming a ring at a desired position.
  • amino acid pair at positions 16 and 20 of the peptide may be substituted with glutamic acid or lysine capable of forming a ring, respectively, but is not limited thereto.
  • Such a ring may be formed between amino acid side chains in the peptide, for example, a lactam ring may be formed between a lysine side chain and a glutamic acid side chain, but is not particularly limited thereto.
  • the amino acid sequence is different from that of native glucagon by one or more, and the alpha-carbon of the N-terminal amino acid residue has been removed, glucagon receptor, GLP-1 receptor, and activity against GIP receptor
  • amino acids may be substituted with other amino acids or non-natural compounds in order to avoid the recognition action of an activator degrading enzyme in order to increase the half-life in the body.
  • the peptide may be a peptide having an increased half-life in the body by avoiding the recognition action of the degrading enzyme through substitution of the second amino acid sequence among the amino acid sequence of the peptide, but amino acid substitution or change to avoid the recognition action of the degrading enzyme in the body included without limitation.
  • modifications for the production of peptides include modifications with L- or D-form amino acids, and/or non-natural amino acids; and/or by modifying the native sequence, e.g., modification of side chain functional groups, intramolecular covalent bonds, such as inter-side chain ring formation, methylation, acylation, ubiquitination, phosphorylation, aminohexylation, biotinylation, etc. includes all that
  • amino acids to be substituted or added may be atypical or non-naturally occurring amino acids as well as the 20 amino acids commonly observed in human proteins.
  • Commercial sources of atypical amino acids include Sigma-Aldrich, ChemPep and Genzyme Pharmaceuticals. Peptides containing these amino acids and canonical peptide sequences can be synthesized and purchased from commercial peptide synthesis companies, for example, American peptide company or Bachem in the United States, or Anygen in Korea.
  • Amino acid derivatives can also be obtained in the same manner, and 4-imidazoacetic acid can be used, to name just a few examples.
  • the peptide according to the present invention has its N-terminus and/or C-terminus chemically modified or protected by an organic group in order to protect it from proteolytic enzymes in vivo and to increase stability, or amino acids are added to the peptide terminus, etc. It may be added and modified form.
  • the N-terminus is acetylated and/or the C-terminus is amidated to remove these charges.
  • it is not particularly limited thereto.
  • the peptide according to the present invention includes both the peptide itself, a salt thereof (eg, a pharmaceutically acceptable salt of the peptide), or a solvate thereof.
  • the peptide may be in any pharmaceutically acceptable form.
  • the type of the salt is not particularly limited. However, it is preferable that the form is safe and effective for an individual, such as a mammal, but is not particularly limited thereto.
  • pharmaceutically acceptable means a substance that can be effectively used for a desired purpose without causing excessive toxicity, irritation, or allergic reaction within the scope of medical judgment.
  • salts derived from pharmaceutically acceptable inorganic acids, organic acids, or bases include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, formic acid , benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, and the like.
  • Salts derived from suitable bases may include alkali metals such as sodium and potassium, alkaline earth metals such as magnesium, and ammonium.
  • solvate refers to a compound in which the peptide or salt thereof according to the present invention forms a complex with a solvent molecule.
  • the peptide (triple agonist), or Z of Formula 1 may include an amino acid sequence represented by Formula 1 below.
  • Xaa1 is histidine, 4-imidazoacetyl, or tyrosine;
  • Xaa2 is glycine, alpha-methyl-glutamic acid, or Aib;
  • Xaa3 is glutamic acid or glutamine
  • Xaa7 is threonine or isoleucine
  • Xaa10 is leucine, tyrosine, lysine, cysteine, or valine;
  • Xaa12 is lysine, serine, or isoleucine
  • Xaa13 is glutamine, tyrosine, alanine, or cysteine;
  • Xaa14 is leucine, methionine, or tyrosine
  • Xaa15 is cysteine, aspartic acid, glutamic acid, or leucine
  • Xaa16 is glycine, glutamic acid, or serine
  • Xaa17 is glutamine, arginine, isoleucine, glutamic acid, cysteine, or lysine;
  • Xaa18 is alanine, glutamine, arginine, or histidine;
  • Xaa19 is alanine, glutamine, cysteine, or valine;
  • Xaa20 is lysine, glutamine, or arginine
  • Xaa21 is glutamic acid, glutamine, leucine, cysteine, or aspartic acid;
  • Xaa23 is isoleucine or valine
  • Xaa24 is alanine, glutamine, cysteine, asparagine, aspartic acid, or glutamic acid,
  • Xaa27 is valine, leucine, or lysine
  • Xaa28 is cysteine, lysine, alanine, asparagine, or aspartic acid
  • Xaa29 is cysteine, glycine, glutamine, threonine, glutamic acid, or histidine;
  • Xaa30 is cysteine, glycine, lysine, or histidine, or is absent;
  • R1 is cysteine, GKKNDWKHNIT (SEQ ID NO: 106), m-SSGAPPPS-n (SEQ ID NO: 107), or m-SSGQPPPS-n (SEQ ID NO: 108), or is absent;
  • m is -Cys-, -Pro-, or -Gly-Pro-;
  • n is -Cys-, -Gly-, -Ser-, or -His-Gly-, or absent.
  • SEQ ID NO: 12 may be exceptionally methionine.
  • triple activator triple activator or Z of Formula 1
  • SEQ ID NOs: 1 to 11, 13 to 102 may be configured (essentially) of an amino acid sequence selected from the group consisting of, but is not limited thereto.
  • the triple active agent (triple agent) or Z of Formula 1 is SEQ ID NO: 21, 22, 42, 43, 50, 64, 66, 67, 70, 71, 76, 77, 96, It may include or (essentially) an amino acid sequence selected from the group consisting of 97 and 100, but is not limited thereto.
  • the triple active agent (triple agent) or Z of Formula 1 is selected from the group consisting of SEQ ID NOs: 21, 22, 42, 43, 50, 66, 67, 77, 96, 97 and 100 It may include or (essentially) consist of an amino acid sequence, but is not limited thereto.
  • the triple activator (triple agonist) or Z of Formula 1 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 21, 22, 42, 43, 50, 77 and 96, or (essential ), but is not limited thereto.
  • Xaa14 may be leucine or methionine
  • Xaa15 may be cysteine, aspartic acid, or leucine.
  • a peptide examples include, but are not particularly limited to, a peptide comprising or (essentially) consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 11, 14 to 17, and 21 to 102.
  • Such a peptide may significantly activate one or more of a glucagon receptor, a GLP-1 receptor, and a GIP receptor, but is not particularly limited thereto. Specifically, it may significantly activate GLP-1 or further significantly activate glucagon receptor and/or GIP receptor, but is not particularly limited thereto.
  • Xaa2 is glycine, alpha-methyl-glutamic acid, or Aib;
  • Xaa7 is threonine
  • Xaa10 is tyrosine, cysteine, or valine
  • Xaa12 is lysine or isoleucine
  • Xaa13 is tyrosine, alanine, glutamine, or cysteine
  • Xaa14 is leucine, tyrosine, or methionine
  • Xaa15 is cysteine, leucine, glutamic acid, or aspartic acid
  • Xaa17 is glutamine, arginine, isoleucine, cysteine, glutamic acid, or lysine;
  • Xaa18 is alanine, glutamine, arginine, or histidine;
  • Xaa19 is alanine, glutamine, valine, or cysteine
  • Xaa20 is lysine, arginine, or glutamine
  • Xaa21 is glutamic acid, glutamine, leucine, cysteine, or aspartic acid;
  • Xaa23 is isoleucine or valine
  • Xaa24 is cysteine, alanine, glutamine, asparagine, glutamic acid, or aspartic acid;
  • Xaa27 may be a peptide, which is leucine or lysine, but is not particularly limited thereto.
  • Xaa2 is glycine, alpha-methyl-glutamic acid, or Aib;
  • Xaa7 is threonine
  • Xaa10 is tyrosine, cysteine, or valine
  • Xaa12 is lysine or isoleucine
  • Xaa13 is tyrosine, alanine, or cysteine
  • Xaa14 is leucine or methionine
  • Xaa15 is cysteine or aspartic acid
  • Xaa17 is glutamine, arginine, isoleucine, cysteine, or lysine;
  • Xaa18 is alanine, arginine, or histidine
  • Xaa19 is alanine, glutamine, or cysteine
  • Xaa20 is lysine or glutamine
  • Xaa21 is glutamic acid, cysteine, or aspartic acid
  • Xaa23 is valine
  • Xaa24 is alanine, glutamine, cysteine, asparagine, or aspartic acid
  • Xaa27 may be leucine or lysine, but is not particularly limited thereto.
  • Xaa2 is alpha-methyl-glutamic acid or Aib
  • Xaa7 is threonine
  • Xaa10 is tyrosine or cysteine
  • Xaa12 is lysine or isoleucine
  • Xaa13 is tyrosine, alanine, or cysteine
  • Xaa14 is leucine or methionine
  • Xaa15 is cysteine or aspartic acid
  • Xaa16 is glutamic acid
  • Xaa17 is arginine, isoleucine, cysteine, or lysine;
  • Xaa18 is alanine, arginine, or histidine
  • Xaa19 is alanine, glutamine, or cysteine
  • Xaa20 is lysine or glutamine
  • Xaa21 is glutamic acid or aspartic acid
  • Xaa23 is valine
  • Xaa24 is glutamine, asparagine, or aspartic acid
  • Xaa27 is leucine
  • Xaa28 may be cysteine, alanine, asparagine, or aspartic acid.
  • Xaa1 is histidine or 4-imidazoacetyl
  • Xaa2 is alpha-methyl-glutamic acid or Aib
  • Xaa3 is glutamine
  • Xaa7 is threonine
  • Xaa10 is tyrosine
  • Xaa12 is isoleucine
  • Xaa13 is alanine or cysteine
  • Xaa14 is methionine
  • Xaa15 is aspartic acid
  • Xaa16 is glutamic acid
  • Xaa17 is isoleucine or lysine
  • Xaa18 is alanine or histidine
  • Xaa19 is glutamine or cysteine
  • Xaa20 is lysine
  • Xaa21 is aspartic acid
  • Xaa23 is valine
  • Xaa24 is asparagine
  • Xaa27 is leucine
  • Xaa28 is alanine or asparagine
  • Xaa29 is glutamine or threonine
  • Xaa30 may be cysteine or lysine or absent.
  • Xaa2 is glycine, alpha-methyl-glutamic acid, or Aib;
  • Xaa3 is glutamine
  • Xaa7 is threonine
  • Xaa10 is tyrosine, cysteine, or valine
  • Xaa12 is lysine
  • Xaa13 is tyrosine
  • Xaa14 is leucine
  • Xaa15 is aspartic acid
  • Xaa16 is glycine, glutamic acid, or serine
  • Xaa17 is glutamine, arginine, cysteine, or lysine
  • Xaa18 is alanine, arginine, or histidine
  • Xaa19 is alanine or glutamine
  • Xaa20 is lysine or glutamine
  • Xaa21 is glutamic acid, cysteine, or aspartic acid
  • Xaa23 is valine
  • Xaa24 is alanine, glutamine, or cysteine
  • Xaa27 is leucine or lysine
  • Xaa29 may be glycine, glutamine, threonine, or histidine, but is not particularly limited thereto.
  • These peptides have significant activation levels of GLP-1 receptors and glucagon receptors, and are higher than those of GIP receptors;
  • the activation levels of the GLP-1 receptor, the glucagon receptor and the GIP receptor are all significant;
  • the degree of activation of the GLP-1 receptor and the GIP receptor is significant and may correspond to a case where the activation level of the glucagon receptor is higher than that of the glucagon receptor, but is not particularly limited thereto.
  • Such peptides include SEQ ID NOs: 8, 9, 21 to 37, 39, 42, 43, 49 to 61, 64 to 83, 85, 86, 88, 89, 91 to 93, selected from the group consisting of 95 to 102 and a peptide comprising or (essentially) consisting of an amino acid sequence, but is not particularly limited thereto.
  • the peptide may include an amino acid sequence represented by the following general formula (2).
  • Xaa1 is 4-imidazoacetyl, histidine, or tyrosine;
  • Xaa2 is glycine, alpha-methyl-glutamic acid, or Aib;
  • Xaa10 is tyrosine or cysteine
  • Xaa13 is alanine, glutamine, tyrosine, or cysteine;
  • Xaa14 is leucine, methionine, or tyrosine
  • Xaa15 is aspartic acid, glutamic acid, or leucine
  • Xaa16 is glycine, glutamic acid, or serine
  • Xaa17 is glutamine, arginine, isoleucine, glutamic acid, cysteine, or lysine;
  • Xaa18 is alanine, glutamine, arginine, or histidine;
  • Xaa19 is alanine, glutamine, cysteine, or valine;
  • Xaa20 is lysine, glutamine, or arginine
  • Xaa21 is cysteine, glutamic acid, glutamine, leucine, or aspartic acid;
  • Xaa23 is isoleucine or valine
  • Xaa24 is cysteine, alanine, glutamine, asparagine, or glutamic acid
  • Xaa28 is lysine, cysteine, asparagine, or aspartic acid
  • Xaa29 is glycine, glutamine, cysteine, or histidine
  • Xaa30 is cysteine, glycine, lysine, or histidine
  • Xaa31 is proline or cysteine
  • Xaa40 is cysteine or absent.
  • Xaa13 is alanine, tyrosine, or cysteine
  • Xaa15 is aspartic acid or glutamic acid
  • Xaa17 is glutamine, arginine, cysteine, or lysine
  • Xaa18 is alanine, arginine, or histidine
  • Xaa21 is cysteine, glutamic acid, glutamine, or aspartic acid
  • Xaa23 is isoleucine or valine
  • Xaa24 is cysteine, glutamine, or asparagine
  • Xaa28 is cysteine, asparagine, or aspartic acid
  • Xaa29 is glutamine, cysteine, or histidine
  • Xaa30 may be cysteine, lysine, or histidine.
  • Examples of such a peptide include an amino acid sequence selected from the group consisting of SEQ ID NOs: 21, 22, 42, 43, 50, 64 to 77, and 95 to 102, or SEQ ID NOs: 21, 22, 42, 43, 50, 64 to 77, and a peptide comprising or (essentially) consisting of an amino acid sequence selected from the group consisting of 96 to 102, but is not particularly limited thereto.
  • the peptide may include an amino acid sequence of the following general formula (3).
  • Xaa1 is histidine or tyrosine
  • Xaa2 is alpha-methyl-glutamic acid or Aib
  • Xaa13 is alanine, tyrosine or cysteine
  • Xaa17 is arginine, cysteine, or lysine
  • Xaa18 is alanine or arginine
  • Xaa19 is alanine or cysteine
  • Xaa21 is glutamic acid or aspartic acid
  • Xaa24 is glutamine or asparagine
  • Xaa28 is cysteine or aspartic acid
  • Xaa29 is cysteine, histidine, or glutamine
  • Xaa30 is cysteine or histidine
  • Xaa31 is proline or cysteine
  • Xaa40 may be cysteine or absent.
  • peptides examples include peptides comprising or (essentially) consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs: 21, 22, 42, 43, 50, 64 to 71, 75 to 77, and 96 to 102. However, it is not particularly limited thereto.
  • R1 is cysteine, GKKNDWKHNIT (SEQ ID NO: 106), CSSGQPPPS (SEQ ID NO: 109), GPSSGAPPPS (SEQ ID NO: 110), GPSSGAPPPSC (SEQ ID NO: 111), PSSGAPPPS (SEQ ID NO: 112), PSSGAPPPSG (SEQ ID NO: SEQ ID NO: 110) 113), PSSGAPPPSHG (SEQ ID NO: 114), PSSGAPPPSS (SEQ ID NO: 115), PSSGQPPPS (SEQ ID NO: 116), or PSSGQPPPSC (SEQ ID NO: 117), or absent, but is not particularly limited thereto.
  • the length of the peptide of the present invention can be synthesized by a method well known in the art, for example, an automatic peptide synthesizer, or it can be produced by a genetic engineering technique.
  • the peptides of the present invention can be prepared by standard synthetic methods, recombinant expression systems, or any other method in the art.
  • the peptides according to the invention can be synthesized in a number of ways, including, for example, those comprising:
  • a method for obtaining a fragment of a peptide by any combination of (a), (b) and (c), and then ligating the fragments to obtain a peptide, and recovering the peptide.
  • the triple-acting long-acting binder or the triple-acting agent may be non-naturally occurring.
  • the triple-functional long-acting conjugate may be a conjugate represented by Formula 1 described above, but is not limited thereto.
  • Lx is a linker containing an ethylene glycol repeating unit, and x is 0 or a natural number
  • Fc is an immunoglobulin Fc region
  • Z is as described above. Z may mean triple agonist.
  • Fc is a substance capable of increasing the half-life of a peptide, having activity against Z, that is, glucagon receptor, GLP-1 receptor, and GIP receptor, in one component of the moiety constituting the conjugate of the present invention. corresponds to
  • the Fc may be bonded to each other by a covalent chemical bond or a non-covalent chemical bond with Z, and Fc and Z may be bonded to each other through Lx by a covalent chemical bond, a non-covalent chemical bond, or a combination thereof.
  • the Fc may be directly linked to Z (ie, x is 0 in Formula 1) or linked through a linker (Lx).
  • Lx may be a non-peptidyl linker, for example, a linker containing an ethylene glycol repeating unit.
  • non-peptidyl linker includes a biocompatible polymer in which two or more repeating units are bonded. The repeating units are linked to each other through any covalent bond other than a peptide bond.
  • the non-peptidyl linker may be one component constituting a moiety of the conjugate of the present invention, and corresponds to Lx in Formula 1 above.
  • x may be 1 or more, and when x is 2 or more, each L may be independent.
  • the non-peptidyl linker that can be used in the present invention may be used without limitation as long as it is a polymer resistant to proteolytic enzymes in vivo.
  • the non-peptidyl linker may be used in combination with a non-peptidyl polymer.
  • non-peptidyl linker may be a linker containing an ethylene glycol repeating unit, for example, polyethylene glycol, and also derivatives thereof known in the art and easily at the level of skill in the art. Derivatives that can be prepared are also included in the scope of the present invention.
  • the repeating unit of the non-peptidyl linker may be an ethylene glycol repeating unit, and specifically, the non-peptidyl linker may include an ethylene glycol repeating unit and a functional group used in the preparation of the conjugate at the terminal thereof.
  • the long-acting conjugate according to the present invention may be in a form in which Z and Fc are linked through the functional group, but is not limited thereto.
  • the non-peptidyl linker may include two, or three or more functional groups, and each functional group may be the same or different from each other, but is not limited thereto.
  • the linker may be polyethylene glycol (PEG) represented by the following formula (2), but is not limited thereto:
  • the PEG moiety in the long-acting conjugate may include, but is not limited to, the -(CH2CH2O)n- structure as well as an oxygen atom intervening between the linking element and the -(CH2CH2O)n-.
  • the conjugate comprises a peptide (Z) comprising the amino acid sequence of Formula 1 or an amino acid sequence of any one of SEQ ID NOs: 1 to 102 and an immunoglobulin Fc region (Fc) comprising an ethylene glycol repeating unit It may be a structure connected by a covalent bond through a linker containing it, but is not limited thereto.
  • the polyethylene glycol is a term encompassing all forms of ethylene glycol homopolymer, PEG copolymer, or monomethyl-substituted PEG polymer (mPEG), but is not particularly limited thereto.
  • the ethylene glycol repeating unit may be represented by, for example, [OCH 2 CH 2 ]n, and the value of n is a natural number, the average molecular weight of the [OCH 2 CH 2 ]n site in the peptide conjugate, such as the number
  • the average molecular weight may be set to be greater than 0 to about 100 kDa, but is not limited thereto.
  • the n value is a natural number
  • the average molecular weight of the [OCH 2 CH 2 ]n site in the peptide conjugate for example, has a number average molecular weight of about 1 to about 100 kDa, about 1 to about 80 kDa, about 1 to about 50 kDa, about 1 to about 30 kDa, about 1 to about 25 kDa, about 1 to about 20 kDa, about 1 to about 15 kDa, about 1 to about 13 kDa, about 1 to about 11 kDa, about 1 to about 10 kDa, about 1 to about 8 kDa, about 1 to about 5 kDa, about 1 to about 3.4 kDa, about 3 to about 30 kDa, about 3 to about 27 kDa, about 3 to about 25 kDa, about 3 to about 22 kDa , about 3 to about 20 kDa, about 3 to about 18 kDa, about 3 to about 16 kDa
  • the non-peptidyl linker that can be used in the present invention may be used without limitation as long as it is a polymer including an ethylene glycol repeating unit resistant to proteolytic enzymes in vivo.
  • the molecular weight of the non-peptidyl polymer is, but is not limited to, greater than 0, in the range of about 100 kDa, in the range of about 1 to about 100 kDa, specifically in the range of about 1 to about 20 kDa, or in the range of about 1 to about 10 kDa.
  • a combination of different types of polymers as well as one type of polymer may be used for the non-peptidyl linker of the present invention that is coupled to the polypeptide corresponding to the Fc.
  • both ends of the non-peptidyl linker are each Fc, such as an amine group, a thiol group, a hydroxyl group, and an amine group, a thiol group, an azide group, and a hydroxyl group of an immunoglobulin Fc region. It may be combined, but is not limited thereto.
  • the non-peptidyl polymer has a reactive group capable of binding to Fc (eg, immunoglobulin Fc region) and Z, respectively, at both ends, specifically, a thiol group of a cysteine in the immunoglobulin Fc region; an amine group located at the N-terminus, lysine, arginine, glutamine and/or histidine; and/or bonded to a hydroxyl group located at the C-terminus, and a thiol group of cysteine of Z; amine groups of lysine, arginine, glutamine and/or histidine; azide group of azidolysin; and/or a reactive group capable of bonding to a hydroxyl group, but is not limited thereto.
  • Fc immunoglobulin Fc region
  • Z a reactive group capable of binding to Fc (eg, immunoglobulin Fc region) and Z, respectively, at both ends, specifically, a thiol group of a cysteine in the immuno
  • both ends of the non-peptidyl linker may be respectively bound to an amine or thiol group of an Fc region, such as an immunoglobulin Fc region, and an amine or thiol group of Z.
  • the non-peptidyl polymer has a reactive group capable of binding to Fc (eg, immunoglobulin Fc region) and Z, respectively, at both ends, specifically Z, or the N-terminus of Fc (eg, immunoglobulin Fc region).
  • Fc eg, immunoglobulin Fc region
  • Z the N-terminus of Fc
  • it may include a reactive group capable of bonding to an amine group located on lysine, or a thiol group of cysteine, but is not limited thereto.
  • the reactive group of the non-peptide polymer capable of binding to Fc may be at least one selected from the group consisting of an aldehyde group, a maleimide group and a succinimide derivative, but is not limited thereto. .
  • the aldehyde group may be exemplified by a propionaldehyde group or a butyl aldehyde group, but is not limited thereto.
  • succinimidyl valerate succinimidyl methylbutanoate, succinimidyl methylpropionate, succinimidyl butanoate, succinimidyl propionate, N-hydroxysuccini Mead, hydroxy succinimidyl, succinimidyl carboxymethyl or succinimidyl carbonate may be used, but are not limited thereto.
  • the non-peptide linker may be connected to Z and Fc through such a reactive group and converted into a non-peptide linker linkage, but is not particularly limited thereto.
  • the final product resulting from reductive amination by aldehyde bonds is much more stable than those linked by amide bonds.
  • the aldehyde reactive group selectively reacts with the N-terminus at a low pH, and can form a covalent bond with a lysine residue at a high pH, for example, pH 9.0.
  • the reactive groups at both ends of the non-peptidyl linker may be the same or different from each other, for example, a maleimide group at one end and an aldehyde group, a propionaldehyde group, or a butyl aldehyde group at the other end.
  • Fc specifically, immunoglobulin Fc region and Z can be bound to each end of the non-peptidyl linker, it is not particularly limited thereto.
  • one end of the non-peptidyl linker may include a maleimide group as a reactive group, and an aldehyde group, a propionaldehyde group, or a butyl aldehyde group at the other end of the non-peptidyl linker.
  • the hydroxyl group can be activated into the various reactive groups by a known chemical reaction, or a commercially available polyethylene glycol having a modified reactive group is used.
  • the long-acting protein conjugate of the invention can be prepared.
  • the non-peptidyl polymer may be linked to a cysteine residue of Z, more specifically, a -SH group of cysteine, but is not limited thereto.
  • cysteine residue 10 cysteine 13, cysteine 15, cysteine 17, cysteine 19, cysteine 21, cysteine 24, cysteine 28, 29
  • the non-peptidyl polymer may be linked to cysteine residue No. 30, cysteine residue 30, cysteine 31, cysteine 40, or cysteine 41, but is not particularly limited thereto.
  • a reactive group of the non-peptidyl polymer may be linked to the -SH group of the cysteine residue, and all of the above descriptions apply to the reactive group.
  • maleimide-PEG-aldehyde is used, the maleimide group is linked to the -SH group of Z by a thioether bond, and the aldehyde group is Fc, specifically, the -NH 2 group of immunoglobulin Fc reductive amination reaction may be connected through, but is not limited thereto, and this corresponds to one example.
  • the N-terminal amino group of the immunoglobulin Fc region is linked to an oxygen atom located at one end of PEG, a non-peptidyl polymer, through a linker functional group having the structure -CH 2 CH 2 CH 2 - , -PEG-O-CH 2 CH 2 CH 2 NH-Can form the same structure as immunoglobulin Fc, and one end of PEG through a thioether bond is a sequence of any one of Formula 1 or SEQ ID NOs: 1 to 102 It can form a structure linked to the sulfur atom located at the cysteine of the peptide containing.
  • the above-mentioned thioether bond is may contain the structure of
  • the non-peptidyl polymer may be linked to a lysine residue of Z, more specifically, an amino group of lysine, but is not limited thereto.
  • the reactive group of the non-peptidyl polymer may be linked to -NH 2 located at the N-terminus of the immunoglobulin Fc region, but this corresponds to one example.
  • the peptide may be linked to a linker having a reactive group through the C-terminus, but this corresponds to one example.
  • C-terminus refers to the carboxy terminus of a peptide, and refers to a position capable of binding to a linker for the purpose of the present invention.
  • it may include all amino acid residues around the C-terminus as well as the most terminal amino acid residue at the C-terminus, and specifically includes the first to 20th amino acid residues from the most terminal. can, but is not limited thereto.
  • the Fc may be an immunoglobulin Fc region, and more specifically, the immunoglobulin Fc region may be derived from IgG, but is not particularly limited thereto.
  • immunoglobulin Fc region refers to a region including heavy chain constant region 2 (CH2) and/or heavy chain constant region 3 (CH3), excluding the heavy and light chain variable regions of immunoglobulin.
  • the immunoglobulin Fc region may be one component constituting a moiety of the conjugate of the present invention.
  • the immunoglobulin Fc region may be used interchangeably with “immunoglobulin Fc fragment”.
  • the Fc region not only the native sequence obtained from papain digestion of immunoglobulin, but also its derivatives, such as one or more amino acid residues in the native sequence, are converted by deletion, insertion, non-conservative or conservative substitution, or a combination thereof, resulting in a native natural sequence. It encompasses and includes sequences that differ from the type.
  • the Fc has a structure in which two polypeptide chains are linked by a disulfide bond, and may have a structure in which only one of the two chains is linked through a nitrogen atom, but is not limited thereto.
  • the linkage via the nitrogen atom may be linked via reductive amination to the epsilon amino atom or the N-terminal amino group of lysine.
  • Reductive amination reaction refers to a reaction in which an amine group or an amino group of a reactant reacts with an aldehyde (that is, a functional group capable of reductive amination) of another reactant to form an amine, and then forms an amine bond by a reduction reaction, It is an organic synthesis reaction well known in the art.
  • the Fc may be linked through the nitrogen atom of its N-terminal proline, but is not limited thereto.
  • the immunoglobulin Fc region is one component constituting a moiety of the conjugate of Formula 1 of the present invention, and specifically, may correspond to Fc in Formula 1 above.
  • the immunoglobulin Fc region may include a hinge region in the heavy chain constant region, but is not limited thereto.
  • the immunoglobulin Fc region may include a specific hinge sequence at the N-terminus.
  • flankinge sequence refers to a region that is located on a heavy chain and forms a dimer of an immunoglobulin Fc region through an inter disulfide bond.
  • the hinge sequence may be mutated to have only one cysteine residue by deleting a portion of the hinge sequence having the following amino acid sequence, but is not limited thereto:
  • the hinge sequence may include only one cysteine residue by deleting the 8th or 11th cysteine residue in the hinge sequence of SEQ ID NO: 118.
  • the hinge sequence of the present invention may be composed of 3 to 12 amino acids, including only one cysteine residue, but is not limited thereto.
  • the hinge sequence of the present invention may have the following sequences: Glu-Ser-Lys-Tyr-Gly-Pro-Pro-Pro-Ser-Cys-Pro (SEQ ID NO: 119), Glu-Ser- Lys-Tyr-Gly-Pro-Pro-Cys-Pro-Ser-Pro (SEQ ID NO: 120), Glu-Ser-Lys-Tyr-Gly-Pro-Pro-Cys-Pro-Ser (SEQ ID NO: 121), Glu- Ser-Lys-Tyr-Gly-Pro-Pro-Cys-Pro-Pro (SEQ ID NO: 122), Lys-Tyr-Gly-Pro-Pro-Cys-Pro-Ser (SEQ ID NO: 123), Glu-Ser-Lys- Tyr-Gly-Pro-Pro-Cys (SEQ ID NO: 124), Glu-Lys-Tyr-Gly-Pro-Pro-Cys (SEQ ID NO
  • the hinge sequence may include the amino acid sequence of SEQ ID NO: 128 (Pro-Ser-Cys-Pro) or SEQ ID NO: 137 (Ser-Cys-Pro), but is not limited thereto.
  • the immunoglobulin Fc region of the present invention may be in a form in which two immunoglobulin Fc chain molecules form a dimer due to the presence of a hinge sequence.
  • one end of the linker is a dimer immunoglobulin It may be in a form linked to one chain of the Fc region, but is not limited thereto.
  • N-terminus refers to the amino terminus of a protein or polypeptide, and 1, 2, 3, 4, 5, 6, It may include up to 7, 8, 9, or 10 or more amino acids.
  • the immunoglobulin Fc region of the present invention may include a hinge sequence at the N-terminus, but is not limited thereto.
  • part or all of the heavy chain constant region 1 (CH1) and/or the light chain constant region except for only the heavy and light chain variable regions of immunoglobulin 1 (CL1) may be an extended Fc region. Also, it may be a region in which some fairly long amino acid sequences corresponding to CH2 and/or CH3 have been removed.
  • the immunoglobulin Fc region of the present invention comprises 1) a CH1 domain, a CH2 domain, a CH3 domain and a CH4 domain, 2) a CH1 domain and a CH2 domain, 3) a CH1 domain and a CH3 domain, 4) a CH2 domain and a CH3 domain, 5) a combination of one or two or more domains of CH1 domain, CH2 domain, CH3 domain and CH4 domain with an immunoglobulin hinge region (or a part of the hinge region), 6) heavy chain constant region Each domain may be a dimer of a light chain constant region .
  • the present invention is not limited thereto.
  • the immunoglobulin Fc region may be in a dimeric form, and one molecule of Z may be covalently linked to one Fc region in a dimeric form, in which case the immunoglobulin Fc and Z may be covalently linked to each other through a linker containing an ethylene glycol repeating unit.
  • the immunoglobulin Fc and Z may be linked to each other by a linker containing an ethylene glycol repeating unit.
  • Z may be covalently linked via a linker Lx to only one of the two polypeptide chains of the Fc region dimer Fc.
  • Lx linker
  • the Fc region dimer Fc only one molecule of Z may be covalently linked via Lx to one polypeptide chain to which Z is linked.
  • the Fc may be a homodimer.
  • the immunoglobulin Fc region Fc is a dimer consisting of two polypeptide chains, and one end of Lx may be connected to only one of the two polypeptide chains, but is not limited thereto. does not
  • the immunoglobulin Fc region of the present invention includes a native amino acid sequence as well as a sequence derivative thereof.
  • An amino acid sequence derivative means that one or more amino acid residues in a natural amino acid sequence have a different sequence by deletion, insertion, non-conservative or conservative substitution, or a combination thereof.
  • amino acid residues 214 to 238, 297 to 299, 318 to 322, or 327 to 331 known to be important for binding may be used as suitable sites for modification.
  • various types of derivatives are possible, such as a site capable of forming a disulfide bond is removed, some amino acids at the N-terminus of native Fc are removed, or a methionine residue may be added to the N-terminus of native Fc do.
  • the complement binding site eg, the C1q binding site
  • the ADCC antibody dependent cell mediated cytotoxicity
  • the above-described Fc derivative may exhibit biological activity equivalent to that of the Fc region of the present invention, and may have increased structural stability to heat, pH, etc. of the Fc region.
  • the Fc region may be obtained from a native type isolated in vivo from animals such as humans, cows, goats, pigs, mice, rabbits, hamsters, rats or guinea pigs, or obtained from transformed animal cells or microorganisms. It may be recombinant or a derivative thereof.
  • the method of obtaining from the native type may be a method of obtaining whole immunoglobulin by isolating it from a living body of a human or animal and then treating it with a proteolytic enzyme. When treated with papain, it is cleaved into Fab and Fc, and when treated with pepsin, it is cleaved into pF'c and F(ab) 2 .
  • Fc or pF'c may be separated using size-exclusion chromatography or the like.
  • it is a recombinant immunoglobulin Fc region obtained by obtaining a human-derived Fc region from a microorganism.
  • the immunoglobulin Fc region may have a native sugar chain, an increased sugar chain compared to the native type, a decreased sugar chain compared to the native type, or a form in which the sugar chain is removed.
  • Conventional methods such as chemical methods, enzymatic methods, and genetic engineering methods using microorganisms may be used for the increase or decrease or removal of such immunoglobulin Fc sugar chains.
  • the immunoglobulin Fc region from which the sugar chains are removed from the Fc has significantly reduced binding to complement (c1q) and reduced or eliminated antibody-dependent cytotoxicity or complement-dependent cytotoxicity, so that unnecessary immune responses in vivo are not induced. does not In this respect, a form more suitable for the original purpose as a drug carrier will be an immunoglobulin Fc region in which sugar chains are removed or non-glycosylated.
  • deglycosylation refers to an Fc region from which sugars have been removed with an enzyme
  • aglycosylation refers to an Fc region that is not glycosylated by production in prokaryotes, in a more specific embodiment, in E. coli. .
  • the immunoglobulin Fc region may be of human or animal origin, such as cattle, goats, pigs, mice, rabbits, hamsters, rats, and guinea pigs, and in a more specific embodiment, it is of human origin.
  • the immunoglobulin Fc region may be an Fc region derived from IgG, IgA, IgD, IgE, or IgM, or a combination or hybrid thereof. In a more specific embodiment, it is derived from IgG or IgM, which is most abundant in human blood, and in a more specific embodiment, it is derived from IgG, which is known to enhance the half-life of ligand binding proteins. In an even more specific embodiment, the immunoglobulin Fc region is an IgG4 Fc region, and in the most specific embodiment, the immunoglobulin Fc region is a non-glycosylated Fc region derived from human IgG4, but is not limited thereto.
  • the immunoglobulin Fc fragment is a fragment of human IgG4 Fc, and is a homologous type in which two monomers are linked through a disulfide bond (inter-chain form) between cysteine, amino acid 3 of each monomer. It may be in the form of a dimer, wherein each monomer of the homodimer is independently an internal disulfide bond between cysteines at positions 35 and 95 and an internal disulfide bond between cysteines at positions 141 and 199, that is, two internal It may have/have disulfide bonds (intra-chain form).
  • the number of amino acids of each monomer may consist of 221 amino acids, and the amino acids forming the homodimer may consist of a total of 442 amino acids, but is not limited thereto.
  • two monomers having the amino acid sequence of SEQ ID NO: 138 (consisting of 221 amino acids) form a homodimer through a disulfide bond between cysteine, the 3rd amino acid of each monomer, and the homodimer
  • the monomers of may each independently form an internal disulfide bond between cysteines at positions 35 and 95 and an internal disulfide bond between cysteines at positions 141 and 199, but is not limited thereto.
  • the Fc of Formula 1 may include a monomer having the amino acid sequence of SEQ ID NO: 138, and the Fc may be a homodimer of the monomer having the amino acid sequence of SEQ ID NO: 138, but is not limited thereto.
  • the immunoglobulin Fc region may be a homodimer comprising the amino acid sequence of SEQ ID NO: 139 (consisting of 442 amino acids), but is not limited thereto.
  • the term "combination" with respect to an immunoglobulin Fc region means that when a dimer or multimer is formed, a polypeptide encoding a single-chain immunoglobulin Fc region of the same origin binds to a single-chain polypeptide of a different origin. means to form That is, it is possible to prepare a dimer or multimer from two or more fragments selected from the group consisting of IgG Fc, IgA Fc, IgM Fc, IgD Fc and IgE Fc fragment.
  • hybrid is a term meaning that sequences corresponding to immunoglobulin Fc fragments of two or more different origins exist in a single-chain immunoglobulin constant region.
  • various types of hybrids are possible. That is, a hybrid of domains consisting of 1 to 4 domains from the group consisting of CH1, CH2, CH3 and CH4 of IgG Fc, IgM Fc, IgA Fc, IgE Fc and IgD Fc is possible, and may include a hinge.
  • IgG can also be divided into subclasses of IgG1, IgG2, IgG3 and IgG4, and in the present invention, a combination thereof or hybridization thereof is also possible. Specifically, they are subclasses of IgG2 and IgG4, and most specifically, an Fc fragment of IgG4 having little effector function such as complement dependent cytotoxicity (CDC).
  • CDC complement dependent cytotoxicity
  • conjugate may have an increased duration of effect compared to native GLP-1, GIP, or glucagon, or compared to Z in which Fc is not modified. It includes all types of particles and the like, but is not limited thereto.
  • the FXR agonist refers to an agonist of FXR, a nuclear receptor activated by bile acids, also known as Bile acid Receptor (BAR), for the glucagon receptor, GLP-1 receptor, and GIP receptor of the present invention.
  • BAR Bile acid Receptor
  • Substances having an activity (triple agonist) or long-acting combination thereof and used in combination therapy to improve the effect of preventing or treating liver disease compared to alone may be included without limitation.
  • FXR is expressed at key sites of bile acid metabolism, such as the liver, intestine, and kidney, and it affects several metabolic pathways, including bile acids, in a tissue-specific manner.
  • FXR is known to inhibit bile acid production and promote elimination through various mechanisms in the liver and intestine.
  • FXR agonists reduce hepatic triglyceride synthesis to reduce steatosis, inhibit hepatic stellate cell activation to reduce hepatic fibrosis, stimulate FGF15/FGF19 expression (a major regulator of bile acid metabolism), and thereby reduce hepatic insulin sensitivity.
  • the FXR agonist is used in combination therapy together with a substance having activity on the glucagon receptor, GLP-1 receptor, and GIP receptor (triple agonist) or a long-acting conjugate thereof (triple-acting long-acting conjugate) of the present invention.
  • Substances capable of improving the effect of preventing or treating liver disease compared to alone are included without limitation, for example, cafestol, chenodeoxycholic acid, obeticholic acid, fexara Fexaramine, GW 4064, PX104, 6E-CDCA (6-ethyl-chedeoxycholic acid), AKN-083 or Tropifexor, Cilofexor, EDP-305, AGN-242266, AGN-242256, EP-024297, RDX-023, BWL-200, GNF-5120, GS-9674, LMB-763, Px-102, Px-103, M790, M780, M450, M-480, MET-409, MET-642, It may be PX20606, EYP-001, TERN-101, TC-100, or INT-2228.
  • the ACC inhibitor refers to a substance that inhibits acetyla-CoA carboxylase, an enzyme important for the regulation of fatty acid production and metabolism, and is active on the glucagon receptor, GLP-1 receptor, and GIP receptor of the present invention
  • a substance having (triple agonist) or a long-acting conjugate thereof (triple-acting long-acting conjugate) and a substance that can be used in combination therapy with the FXR agonist to prevent or improve the therapeutic effect of liver disease compared to alone may be included without limitation.
  • the ACC inhibitor is a substance having activity on the glucagon receptor, GLP-1 receptor, and GIP receptor of the present invention (triple agonist) or a long-acting conjugate thereof (triple-acting long-acting conjugate), and in combination with an FXR agonist
  • Substances that can be used for therapy and improve the effect of preventing or treating liver disease compared to alone are included without limitation, for example, CP-640186, (4-piperidinyl)-piperazine derivative ((4-piperidinyl) -piperazine derivatives), 1,4-disubstituted cyclohexane derivatives, spirochromanone derivatives, spirolactam derivatives, spirodiamine derivatives, spiropenta Thiophene pyrimidone derivatives including Spiropentacylamide derivatives, Pseudopeptide pyrrolidinedione derivatives, Macrocyclic polyketone derivatives, firsocostat derivatives), amino-
  • the combination, pharmaceutical composition or kit of the present invention can be used for the prevention or treatment of liver disease.
  • prevention refers to (a) a substance having activity on the glucagon receptor, the GLP-1 receptor, and the GIP receptor (triple agonist) or a conjugate thereof (triple action long-acting conjugate) and an FXR agonist; or (b) a substance having activity on the glucagon receptor, the GLP-1 receptor, and the GIP receptor (triple agonist) or a conjugate thereof (triple action long-acting conjugate), a combination comprising an FXR agonist and an ACC inhibitor; or It refers to any action that inhibits or delays the onset of a desired disease, such as liver disease, by administration of the composition, and "treatment” refers to (a) a substance having activity on glucagon receptors, GLP-1 receptors, and GIP receptors (3 heavy agonist) or a conjugate thereof (a triple acting long-acting conjugate) and an FXR agonist; or (b) a substance having activity on the glucagon receptor, the GIP receptor (triple agonist) or
  • the term "administration" means introducing a predetermined substance to a patient by any suitable method, and the route of administration of the composition is not particularly limited thereto, but any general route through which the composition can reach an in vivo target It can be administered through, for example, intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, topical administration, intranasal administration, intrapulmonary administration, rectal administration, etc. can be .
  • liver disease refers to a disease occurring in the liver, and may include metabolic liver disease or liver inflammation, but is not limited thereto.
  • Representative examples of the liver disease include non-alcoholic fatty liver disease or cholestasis liver disease.
  • various liver diseases that cause abnormalities in the tissues and functions of the liver are within the scope of the liver disease of the present invention. can be entered, but is not limited thereto.
  • nonalcoholic fatty liver disease refers to a case in which there is no history of alcohol intake or is accompanied by fatty liver although it is not related to alcohol intake.
  • Fatty liver refers to a phenomenon in which triglycerides are abnormally deposited in liver cells, unlike normal cases. About 5% of a normal liver is composed of adipose tissue, and triglycerides, fatty acids, phospholipids, cholesterol, and cholesterol esters are the main components of fat. If it is more than 5% of the liver weight, it is diagnosed as fatty liver. Fatty liver is caused by disorders in fat metabolism in hepatocytes or defects in the process of transporting excess fat, and mainly occurs due to disorders in fat metabolism in the liver.
  • composition according to the present invention inhibits NAS (NAFLD activity score) reduction and fibrosis, it can be seen that lesions of various diseases included in the nonalcoholic fatty liver disease can be prevented or treated.
  • NAS NAFLD activity score
  • the nonalcoholic fatty liver disease includes simple steatosis, liver inflammation, nonalcoholic fatty liver, nonalcoholic steatohepatitis, cirrhosis, liver fibrosis, liver failure or liver cancer. included without
  • the nonalcoholic fatty liver disease may be at least one disease selected from the group consisting of liver inflammation, nonalcoholic steatohepatitis and liver fibrosis, but the nonalcoholic fatty liver disease prevented or treated with the composition of the present invention is included without limitation.
  • nonalcoholic steatohepatitis is one of nonalcoholic fatty liver disease, and is a representative example of liver disease accompanied by liver cell necrosis, inflammation, and fibrosis.
  • the composition according to the present invention contains NAS (NAFLD activity) score) reduction and suppression of fibrosis to exhibit an effect on nonalcoholic steatohepatitis, specifically, nonalcoholic steatohepatitis with fatty liver, liver fibrosis or cirrhosis; or liver cancer caused by nonalcoholic steatohepatitis
  • NAS NAFLD activity
  • the present invention is not limited thereto.
  • liver inflamation refers to a disease that causes inflammation of the liver as the biggest cause of liver disease, and is divided into acute hepatitis and chronic hepatitis according to the cause and symptoms. Viruses, alcohol, drugs, immune abnormalities, and metabolic diseases are the main causes.
  • liver fibrosis is a result of the wound healing process for repeated liver damage, and unlike liver cirrhosis, it is reversible, consists of thin fibrils, Normal recovery may be possible when the cause of liver damage is eliminated. progresses to cirrhosis of the liver.
  • the composition of the present invention may exhibit a preventive or therapeutic effect on liver fibrosis by reducing the hydroxyproline content in the subject to which the pharmaceutical composition is administered, but is not limited thereto.
  • the conjugate according to the present invention not only has the effect of alleviating the fibrosis of the liver itself, but also can exhibit an effect on diseases accompanying or caused by fibrosis of the liver.
  • liver cirrhosis of the present invention is a chronic disease that occurs while repeating hepatocyte regeneration and increase in fibrous tissue and is pathologically accompanied by necrosis, inflammation and fibrosis, and ultimately liver failure It progresses to liver cirrhosis complications and diseases such as liver cancer, leading to death.
  • liver cirrhosis complications and diseases such as liver cancer, leading to death.
  • it since there are no subjective symptoms in the early stage and it is discovered only at a fairly advanced stage, it is required to rapidly treat liver fibrosis, which is a condition before it evolves into cirrhosis or the like.
  • liver decompensation is due to liver damage or liver disease such as viral hepatitis, cirrhosis, drugs or alcohol, liver function is weakened, and the liver can perform protein synthesis and metabolic functions as normal physiological functions. means no state. It is divided into acute liver failure or chronic liver failure according to the rate of progression, and is known to cause various complications.
  • liver damage or liver disease such as viral hepatitis, cirrhosis, drugs or alcohol
  • liver function is weakened, and the liver can perform protein synthesis and metabolic functions as normal physiological functions. means no state. It is divided into acute liver failure or chronic liver failure according to the rate of progression, and is known to cause various complications.
  • Hepatocellular carcinoma of the present invention means a malignant tumor originating from liver cells, and can be divided into primary liver cancer (hepatocellular carcinoma) arising from hepatocytes itself and metastatic liver cancer in which cancers of other tissues have metastasized to the liver. More than 90% of liver cancers are primary liver cancers. In addition to hepatitis and chronic liver disease, the main causes are alcohol, smoking, and obesity.
  • cholestasis is a condition in which the flow of bile from the liver to the duodenum is slowed or blocked
  • cholestasis liver disease is It is meant to be hampered by conditions such as disease, extended jugular vein nutrition, or side effects of certain medications (eg, some antibiotics). Common signs of cholestasis include fatigue, pruritus (itching), jaundice, and xanthomas (deposition of high cholesterol-rich substances under the skin). The effects of cholestasis are severe and widespread, leading to exacerbation of liver disease into systemic disease, liver failure, and the need for liver transplantation. causes of cholestatic liver disease include acute hepatitis and inflammation of the bile ducts.
  • the cholestatic liver disease may include primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), progressive familial intrahepatic cholestasis (PFIC), and Alagille syndrome (AS), etc. It is not limited thereto.
  • PBC primary biliary cholangitis
  • PSC primary sclerosing cholangitis
  • PFIC progressive familial intrahepatic cholestasis
  • AS Alagille syndrome
  • Primary biliary cirrhosis also known as primary biliary cholangitis (PBC) is a chronic cholestatic liver disease of unknown etiology. Progressive bile duct damage due to portal and periportal inflammation can lead to progressive fibrosis and eventual cirrhosis of the liver. So far, immunological, genetic and environmental factors are known as potential causes of the disease. Primary biliary cirrhosis is mainly seen in middle-aged women, and the symptoms are fatigue, itchiness, or unexplained hyperlipidemia at the initial onset, and may also appear as symptoms of primary biliary cirrhosis.
  • the treatment method for PBC is bile acid therapy using ursodeoxycholic acid (UDSA) and obeticholic acid (OCA).
  • UDSA ursodeoxycholic acid
  • OCA obeticholic acid
  • the mechanism of action of both drugs in PBC is related to their ability to activate FXR and TGFR-5 to exert anti-inflammatory effects.
  • sufficient biochemical responses were not achieved in about 40% of patients treated with UDCA.
  • PSC Primary sclerosing cholangitis
  • liver function tests using blood show elevated alkaline phosphatase levels, elevated aminotransferase levels, and gamma globulinemia, the diagnosis of primary sclerosing cholangitis is indicated.
  • liver transplantation is the only treatment method that can fundamentally treat it.
  • composition according to the present invention may be characterized in that there is no or a relatively low degree of weight gain, which is a side effect of the existing therapeutic agent for nonalcoholic fatty liver disease.
  • the composition may (a) decrease the expression or activity of collagen-1a, a fibrosis marker; (b) decreased expression or activity of TNF-alpha (tumor necrosis factor- ⁇ ), a pro-inflammatory marker; (c) decreased expression or activity of sterol regulatory element binding protein-1c (SREBP-1c), a lipogenesis marker; (d) reduction of triglycerides in the liver; and (e) one or more of the properties of (a) to (e), such as reducing blood cholesterol, to prevent or treat liver disease.
  • the present invention is not limited thereto.
  • composition can reduce NAS (NAFLD activity score) to prevent or treat liver disease, for example, non-alcoholic fatty liver disease.
  • NAS NAFLD activity score
  • the composition can prevent or treat liver disease, for example, non-alcoholic fatty liver disease by reducing hydroxyprolin, which is known as an indicator of fibrosis in liver tissue.
  • the pharmaceutical composition of the present invention may further include a pharmaceutically acceptable carrier, excipient or diluent.
  • a pharmaceutically acceptable carrier excipient or diluent.
  • Such pharmaceutically acceptable carriers, excipients, or diluents may be non-naturally occurring.
  • the term "pharmaceutically acceptable” means a sufficient amount to exhibit a therapeutic effect and does not cause side effects, and the type of disease, the patient's age, weight, health, sex, and the patient's sensitivity to the drug , administration route, administration method, frequency of administration, treatment period, combination or drugs used at the same time can be easily determined by those skilled in the art according to factors well known in the medical field.
  • the pharmaceutical composition including the peptide of the present invention may further include a pharmaceutically acceptable excipient.
  • the excipient is not particularly limited thereto, but in the case of oral administration, a binder, a lubricant, a disintegrant, a solubilizer, a dispersing agent, a stabilizer, a suspending agent, a dye, a flavoring agent, etc. may be used, and in the case of an injection, a buffer, a preservative, An analgesic agent, a solubilizer, an isotonic agent, a stabilizer, etc. can be mixed and used, and in the case of topical administration, a base, excipient, lubricant, preservative, etc. can be used.
  • the formulation of the composition of the present invention can be prepared in various ways by mixing with the pharmaceutically acceptable excipients as described above.
  • it may be prepared in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like, and in the case of injections, it may be prepared in the form of unit dose ampoules or multiple doses.
  • it can be formulated as a solution, suspension, tablet, pill, capsule, sustained release formulation, and the like.
  • suitable carriers, excipients and diluents for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, Microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, or mineral oil may be used.
  • it may further include a filler, an anti-aggregating agent, a lubricant, a wetting agent, a flavoring agent, a preservative, and the like.
  • the pharmaceutical composition of the present invention is any one selected from the group consisting of tablets, pills, powders, granules, capsules, suspensions, internal solutions, emulsions, syrups, sterile aqueous solutions, non-aqueous solvents, freeze-dried preparations and suppositories may have the form of
  • composition is formulated in a dosage form suitable for administration in a patient's body according to a conventional method in the pharmaceutical field, specifically, a formulation useful for administration of a protein drug, and administration commonly used in the art.
  • the triple agonist or its long-acting conjugate can be used by mixing with various pharmaceutically acceptable carriers such as physiological saline or organic solvents, and with glucose, sucrose or dextran to increase stability or absorption.
  • various pharmaceutically acceptable carriers such as physiological saline or organic solvents, and with glucose, sucrose or dextran to increase stability or absorption.
  • Carbohydrates, antioxidants such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers may be used as agents.
  • the dosage and frequency of administration of the pharmaceutical composition of the present invention is determined according to the type of drug as the active ingredient, together with several related factors such as the disease to be treated, the route of administration, the age, sex and weight of the patient, and the severity of the disease. .
  • the composition of the present invention may include the peptide or a long-acting conjugate comprising the same in a pharmaceutically effective amount, but is not limited thereto.
  • the inclusion of the peptide or the long-acting conjugate in a pharmaceutically effective amount means the degree to which the desired pharmacological activity (eg, prevention, improvement or treatment of liver disease) can be obtained due to the peptide or the long-acting conjugate, and also It may mean a pharmaceutically acceptable level as a level that does not cause toxicity or side effects in the administered subject or is insignificant, but is not limited thereto. Such a pharmaceutically effective amount may be determined by comprehensively considering the number of administration, patient, formulation, and the like.
  • the pharmaceutical composition of the present invention may contain the component (active ingredient) in an amount of 0.01 to 99% by weight to volume.
  • the total effective amount of the composition of the present invention may be administered to a patient as a single dose, or may be administered by a fractionated treatment protocol in which multiple doses are administered for a long period of time.
  • the pharmaceutical composition of the present invention may vary the content of the active ingredient according to the severity of the disease.
  • the preferred total dose of the peptide or conjugate of the present invention may be about 0.0001 mg to 500 mg per 1 kg of the patient's body weight per day, but is not limited thereto.
  • the dosage of the conjugate is determined by considering various factors such as the age, weight, health status, sex, severity of disease, diet and excretion rate of the patient, as well as the administration route and number of treatments of the pharmaceutical composition, and the effective dosage for the patient is determined.
  • the pharmaceutical composition according to the present invention is not particularly limited in its formulation, administration route and administration method as long as the effect of the present invention is exhibited.
  • the triple agonist or long-acting conjugate thereof of the present invention may be an FXR agonist; or an FXR agonist and an ACC inhibitor in an appropriate ratio.
  • the triple agent of the present invention or a long-acting conjugate thereof may be administered in an amount of about 0.1 to about 100 mg, about 0.5 to about 80 mg, about 1 to about 60 mg, about 1 to about 25 mg, administered at about 5 to about 20 mg, or about 10 to about 15 mg
  • the FXR agonist is about 1 to about 100 mg, about 1 to about 250 mg, about 5 to about 250 mg, about 5 to about 50 mg, about 5 to about 40 mg, about 5 to about 40 mg, about 5 to about 25 mg, about 5 to about 30 mg, about 90 to about 250 mg, about 140 to about 250 mg, about 140 to about 200 mg
  • the ACC inhibitor is about 1 to 1000 mg, about 5 to about 1000 mg, about 5 to 150 mg, about 5 to about 50 mg, about 5 to about 30 mg, about 5 to about 750
  • the triple agonist or long-acting conjugate thereof of the present invention may be an FXR agonist; Alternatively, it may be administered in combination with an FXR agonist and an ACC inhibitor in an appropriate ratio to exhibit an excellent therapeutic effect on liver disease.
  • the pharmaceutical composition of the present invention has excellent in vivo persistence and potency, and can significantly reduce the number and frequency of administration of the pharmaceutical preparation of the present invention, but is not limited thereto.
  • Another embodiment embodying the present invention is a substance having activity on the glucagon receptor, GLP-1 receptor, and GIP receptor (triple agonist) or a long-acting conjugate thereof (triple), characterized in that it is used in combination with an FXR agonist It provides a pharmaceutical composition for preventing or treating liver disease, including a long-acting long-acting conjugate).
  • the pharmaceutical composition may be further characterized in that it is used in combination with an ACC inhibitor.
  • a substance having activity on the glucagon receptor, the GLP-1 receptor, and the GIP receptor (triple agonist) or a long-acting conjugate thereof (triple-acting long-acting conjugate), an FXR agonist, a composition comprising an ACC agonist, prophylaxis, Treatment, liver disease and pharmaceutical compositions are the same as described above.
  • Another aspect embodying the present invention is (i) a substance having activity on a glucagon receptor, a GLP-1 receptor, and a GIP receptor (triple agonist) or a long-acting conjugate thereof (triple-acting long-acting conjugate), and (ii) administering an FXR agonist to a subject in need thereof.
  • Another aspect embodying the present invention is (i) a substance having activity on a glucagon receptor, a GLP-1 receptor, and a GIP receptor (triple agonist) or a long-acting conjugate thereof (triple-acting long-acting conjugate) , (ii) an FXR agonist, and (iii) an ACC inhibitor to a subject in need thereof.
  • Another aspect embodying the present invention is a pharmaceutically effective amount of (i) a substance having activity on glucagon receptors, GLP-1 receptors, and GIP receptors (triple agonist) or its administering a long-acting conjugate (triple-acting long-acting conjugate); and (ii) administering an FXR agonist, wherein the steps (i) and (ii) are sequential, reversed, or simultaneous.
  • Another aspect embodying the present invention is a pharmaceutically effective amount of (i) a substance having activity on glucagon receptors, GLP-1 receptors, and GIP receptors (triple agonist) or its administering a long-acting conjugate (triple-acting long-acting conjugate); (ii) administering an FXR agonist; and (iii) an ACC inhibitor, wherein the steps of (i), (ii), and (iii) are sequential, reversed, or simultaneous.
  • Each step of administering each active ingredient of the prophylactic or therapeutic method of the present invention may be performed in any order, and (i), (ii), and (iii) do not mean the order, and Each step may be performed sequentially, in reverse order, or simultaneously, but is not limited thereto.
  • a substance having activity on the glucagon receptor, the GLP-1 receptor, and the GIP receptor (triple agonist) or a long-acting conjugate thereof (triple-acting long-acting conjugate), an FXR agonist, a composition comprising an ACC agonist, prophylaxis, Treatment, liver disease and pharmaceutical compositions are the same as described above.
  • the subject is a subject suspected of liver disease
  • the subject suspected of liver disease refers to mammals including mice, livestock, etc. including humans that have or may develop the disease, but the glucagon receptor of the present invention , a substance having activity on the GLP-1 receptor, and the GIP receptor (triple agonist) or a long-acting conjugate thereof (triple-acting long-acting conjugate); and (a) an FXR agonist, or (b) an FXR agonist and an ACC inhibitor.
  • substances having activity on the glucagon receptor, GLP-1 receptor, and GIP receptor of the present invention triple agonist or a long-acting conjugate thereof (triple-acting long-acting conjugate); and (a) an FXR agonist, or (b) an FXR agonist and an ACC inhibitor, by administering to the subject suspected of liver disease, the subject may be efficiently treated.
  • Liver disease is the same as described above.
  • the method of the present invention comprises a substance having activity on the glucagon receptor, the GLP-1 receptor, and the GIP receptor (triple agonist) or a long-acting conjugate thereof (triple-acting long-acting conjugate); and (a) an FXR agonist, or (b) a combination or pharmaceutical composition comprising an FXR agonist and an ACC inhibitor, in a pharmaceutically effective amount.
  • the method according to the present invention comprises a substance having activity on the glucagon receptor, the GLP-1 receptor, and the GIP receptor (triple agonist) or a long-acting conjugate thereof (triple-acting long-acting conjugate); and (a) the FXR agonist, or (b) the FXR agonist and the ACC inhibitor are administered as one agent, or the separate agents are administered simultaneously, separately, sequentially or in reverse order.
  • the term “administration” means introducing a given substance into a patient (individual) by any suitable method.
  • the route of administration of the triple agonist or long-acting conjugate thereof, FXR agonist, or ACC inhibitor is not particularly limited thereto, but the triple agonist or long-acting conjugate thereof, FXR agonist, or any ACC inhibitor capable of reaching an in vivo target It may be administered through a general route, for example, intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, topical administration, intranasal administration, intrapulmonary administration, rectal administration, etc. can be .
  • the triple agonist or long-acting conjugate thereof, FXR agonist, and ACC inhibitor may be administered by the same administration route or may be administered by different administration routes, and the administration routes of the drugs administered in combination are independent of each other can be
  • the triple agonist of the present invention or a long-acting conjugate thereof, an FXR agonist; or a composition comprising a triple agonist or a long-acting combination thereof, an FXR agonist, and an ACC inhibitor once a day, once every 2 days, once every 3 days, once a week, once every two weeks , may be administered once every 4 weeks, or once a month, but is not limited thereto.
  • the FXR agonist and the ACC inhibitor are administered in combination with the triple agonist of the present invention, or a long-acting conjugate thereof, or a composition comprising the same, as long as it can exert a preventive or therapeutic effect on liver disease, but the frequency of administration is not limited, but for example For example, once a day, once every 2 days, once every 3 days, once a week, once every 2 weeks, once every 4 weeks, or once a month.
  • the triple agent or long-acting combination thereof is administered at the same interval, or at a different interval, for example, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days. It may be administered at intervals of one day, or 10 days or more, but is not limited thereto,
  • a suitable total daily amount may be determined by a treating physician within the scope of sound medical judgment, and may be administered once or divided into several doses.
  • a specific therapeutically effective amount for a particular patient depends on the type and extent of the response to be achieved, the specific composition, including whether other agents are used, if necessary, the specific composition, the patient's age, weight, general health, It is preferable to apply differently depending on various factors including sex and diet, administration time, administration route and secretion rate of the composition, treatment period, drugs used together or concurrently with a specific composition, and similar factors well known in the pharmaceutical field.
  • Another aspect embodying the present invention is a liver disease comprising administering and/or using the combination, a pharmaceutical composition for the prevention or treatment of the disease, or the pharmaceutical kit to an individual in need thereof.
  • a method of prevention or treatment is provided.
  • a combination, kit comprising a substance having activity on the glucagon receptor, the GLP-1 receptor, and the GIP receptor (triple agonist) or a long-acting conjugate thereof (triple-acting long-acting conjugate), an FXR agonist, and an ACC agonist , composition, prevention, treatment, liver disease and pharmaceutical composition as described above.
  • Another aspect embodying the present invention provides the use of the combination, pharmaceutical composition, or pharmaceutical kit for the prophylaxis or treatment of liver disease and/or the use of a medicament for the prophylaxis or treatment of liver disease. .
  • a combination, kit comprising a substance having activity on the glucagon receptor, the GLP-1 receptor, and the GIP receptor (triple agonist) or a long-acting conjugate thereof (triple-acting long-acting conjugate), an FXR agonist, and an ACC agonist , composition, prevention, treatment, liver disease and pharmaceutical composition as described above.
  • a triple activator exhibiting activity on all GLP-1 receptors, GIP receptors and glucagon receptors was prepared, and its sequences are shown in Table 1 below.
  • amino acid denoted by X in the sequence shown in Table 1 is Aib (2-aminoisobutyric acid), a non-natural amino acid, and the underlined under the amino acid symbol is the lactam ring between the side chains of the underlined amino acid pair. indicates that it is formed.
  • CA means 4-imidazoacetyl (4-imidazoacetyl).
  • the triple activator of Example 1 (SEQ ID NOs: 21, 22, 42, 43, 50, 77, and 96) for pegylation to the cysteine residues, the molar ratio of the triple activator to maleimide-PEG-aldehyde is 1:1 to 3, and the protein concentration is 1 to 5 mg/ml, and 0.5 to 3 at low temperature. reacted for an hour. At this time, the reaction was carried out in an environment in which 20 to 60% isopropanol was added to 50 mM Tris buffer (pH 7.5).
  • the triple activator was pegylated to the maleimide end of maleimide-PEG-aldehyde by reacting a 10 kDa linearly modified polyethylene glycol, maleimide-PEG-aldehyde (NOF, Japan) with the cysteine residue of the triple activator.
  • reaction solution was applied to SP Sepharose HP (GE healthcare, USA) to purify the tri-activator mono-pegylated to cysteine.
  • the purified mono-pegylated tri-activator and immunoglobulin Fc (homodimer of SEQ ID NO: 138) were mixed in a molar ratio of 1:1 to 5 and a protein concentration of 10 to 50 mg/ml from 4 to The reaction was carried out at 8°C for 12 to 18 hours. The reaction was carried out in an environment in which 10 to 50 mM sodium cyanoborohydride and 10 to 30% isopropanol as reducing agents were added to 100 mM potassium phosphate buffer (pH 6.0).
  • This purified long-acting conjugate has a structure in which a triple active peptide, a polyethylene glycol (PEG) linker and an Fc dimer are covalently linked in a molar ratio of 1:1:1, and the PEG linker is two polypeptide chains of an Fc dimer. It is connected to only one of the chains.
  • PEG polyethylene glycol
  • two monomers having the amino acid sequence of SEQ ID NO: 138 form a homodimer through a disulfide bond between cysteine, which is the 3rd amino acid of each monomer, and the homodimer
  • the monomers of are each independently formed with an internal disulfide bond between cysteines at positions 35 and 95 and an internal disulfide bond between cysteines at positions 141 and 199.
  • the immunoglobulin Fc is an immunoglobulin Fc fragment (a homodimer in which two chains of SEQ ID NO: 138 are linked by a disulfide bond) having a hinge region of the Pro-Ser-Cys-Pro sequence at the N-terminus.
  • International Patent Publication No. WO2007 /021129 was prepared by the method described.
  • conjugate in which the triple activator of SEQ ID NO: 21 and the immunoglobulin Fc are linked via PEG was designated as a 'conjugate comprising SEQ ID NO: 21 and immunoglobulin Fc' or a 'continuous conjugate of SEQ ID NO: 21'. may be used interchangeably.
  • conjugate in which the triple activator of SEQ ID NO: 22 and immunoglobulin Fc are linked via PEG was designated as a 'conjugate comprising SEQ ID NO: 22 and immunoglobulin Fc' or a 'continuous conjugate of SEQ ID NO: 22'. may be used interchangeably.
  • conjugate in which the triple activator of SEQ ID NO: 42 and the immunoglobulin Fc are linked via PEG was designated as a 'conjugate comprising SEQ ID NO: 42 and an immunoglobulin Fc' or a 'continuous conjugate of SEQ ID NO: 42'. may be used interchangeably.
  • conjugate in which the triple activator of SEQ ID NO: 43 and the immunoglobulin Fc are linked via PEG was designated as a 'conjugate comprising SEQ ID NO: 43 and an immunoglobulin Fc' or a 'continuous conjugate of SEQ ID NO: 43', which may be used interchangeably.
  • conjugate in which the triple activator of SEQ ID NO: 50 and immunoglobulin Fc are linked via PEG was named as 'a conjugate comprising SEQ ID NO: 50 and immunoglobulin Fc' or 'a long-acting conjugate of SEQ ID NO: 50', may be used interchangeably.
  • conjugate in which the triple activator of SEQ ID NO: 77 and the immunoglobulin Fc are linked via PEG was designated as a 'conjugate comprising SEQ ID NO: 77 and immunoglobulin Fc' or a 'persistent conjugate of SEQ ID NO: 77' may be used interchangeably.
  • conjugate in which the triple activator of SEQ ID NO: 96 and the immunoglobulin Fc are linked through PEG was designated as a 'conjugate comprising SEQ ID NO: 96 and immunoglobulin Fc' or a 'continuous conjugate of SEQ ID NO: 96'. may be used interchangeably.
  • Example 3 Triple activator and long-acting conjugate thereof in vitro activity measurement
  • Each of the above cell lines was transformed to express human GLP-1 receptor, human GCG receptor and human GIP receptor genes in Chinese hamster ovary (CHO), respectively, and is suitable for measuring the activities of GLP-1, GCG and GIP. Therefore, the activity for each part was measured using each transformed cell line.
  • Human GLP-1 was serially diluted from 50 nM to 0.000048 nM by 4 times to measure the GLP-1 activity of the triple activator and its long-acting conjugate prepared in Examples 1 and 2, and prepared in Examples 1 and 2
  • the triple activator and its long-acting conjugate were serially diluted from 400 nM to 0.00038 nM by 4 times.
  • the culture medium was removed from the cultured CHO cells expressing the human GLP-1 receptor, 5 ⁇ l of each serially diluted substance was added to the cells, and then 5 ⁇ l of a buffer containing cAMP antibody was added for 15 minutes. during incubation at room temperature.
  • human GCG was serially diluted from 50 nM to 0.000048 nM by 4 times, and the triple activator prepared in Examples 1 and 2 was serially diluted. and its long-acting conjugate were serially diluted from 400 nM to 0.00038 nM in 4-fold increments.
  • the culture medium was removed from the cultured CHO cells expressing human GCG receptor, 5 ⁇ l of each serially diluted substance was added to the cells, and 5 ⁇ l of a buffer containing cAMP antibody was added thereto, followed by room temperature for 15 minutes.
  • human GIP was serially diluted from 50 nM to 0.000048 nM by 4 times, and the triple activator prepared in Examples 1 and 2 was serially diluted. and its long-acting conjugate were serially diluted from 400 nM to 0.00038 nM in 4-fold increments.
  • the culture medium was removed from the cultured CHO cells expressing the human GIP receptor, 5 ⁇ l of each serially diluted substance was added to the cells, and 5 ⁇ l of a buffer containing cAMP antibody was added thereto, followed by room temperature for 15 minutes.
  • the triple activator prepared above or a long-acting conjugate thereof has a function as a triple activator capable of activating all of the GLP-1 receptor, the GIP receptor and the glucagon receptor, and thus can be used as a therapeutic substance for a desired disease.
  • NASH and fibrosis model a choline deficient, high fat and high cholesterol diet, known as NASH and fibrosis model
  • induced CD-HFD Choline deficient high fat diet
  • the model was induced by performing CD-HFD in C57BL/6 mice for 8 weeks.
  • a long-acting complex of the triple activator of SEQ ID NO: 42 As a representative example of the long-acting complex of the triple activator, a long-acting complex of the triple activator of SEQ ID NO: 42, cilofexor as a representative example of an FXR agonist, and firsocostat as a representative example of an ACC inhibitor Experiments were performed. Kilopexor and pirsocostat were purchased from MCE (MedChemExpress).
  • the induced animal model was an excipient control group, a long-acting conjugate of the triple activator of SEQ ID NO: 42 (2.6 nmo/kg, Q2D, subcutaneous) single administration group, an FXR agonist single administration group (4.3 mmol/kg, QD, oral), ACC inhibitor Single administration group (51.1 mmol/kg, QD, oral), long-acting conjugate of the triple active agent of SEQ ID NO: 42 (2.6 nmo/kg, Q2D, subcutaneous) and FXR agonist (4.3 mmol/kg, QD, oral) combined administration group, Triple active agent of SEQ ID NO: 42 (2.6 nmo/kg, Q2D, subcutaneous) and ACC inhibitor (51.1 mmol/kg, QD, oral) and FXR agonist (4.3 mmol/kg, QD, oral) triple combination administration group , and repeated administration was carried out for 6 weeks. After 6 weeks of repeated administration, H&E staining was performed on the liver tissue of each mouse taken through auto
  • QD means once a day
  • Q2D means once every two days.
  • the NASH therapeutic efficacy of the triple activator or its long-acting conjugate could be further improved by combined administration with an FXR agonist or triple combination administration with an FXR agonist and an ACC inhibitor.
  • the ACC inhibitor and the triple combination administration of the FXR agonist in liver tissue of the CD-HFD mouse model The content of hydroxyproline, known as an indicator of infiltrating fibrosis, was measured.
  • the long-acting complex of the triple activator of SEQ ID NO: 42 which is a representative example of the long-acting conjugate of the triple activator identified above, the group administered alone, the FXR agonist alone group, the ACC inhibitor alone group, the long-acting type of the triple activator of SEQ ID NO: 42
  • the hydroxyproline content was measured in the liver tissue of the CD-HFD mouse model of the group administered with the conjugate and the FXR agonist, and the long-acting conjugate of the triple activator of SEQ ID NO: 42, and the triple combination administration of the ACC inhibitor and FXR agonist.
  • a long-acting conjugate of the triple activator reduced the hydroxyproline content more than the ACC inhibitor and FXR agonist alone group.
  • the hydroxyproline content significantly decreased by the administration of the long-acting conjugate of the triple activator was more effectively reduced during the combined administration with the FXR agonist and the triple combination administration of the ACC inhibitor and the FXR agonist (Fig. 2).
  • the fibrosis therapeutic efficacy of the triple activator of the present invention or its long-acting conjugate could be more effectively improved by combined administration with an FXR agonist or triple combination administration with an FXR agonist and an ACC inhibitor.
  • the triple active agent or long-acting conjugate of the present invention can further improve the therapeutic effect of various nonalcoholic fatty liver diseases by combined administration with an FXR agonist or triple combination administration with an FXR agonist and an ACC inhibitor. This suggests that it can be used as a new combination dosage formulation, or a triple combination dosage formulation.

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Abstract

La présente invention concerne une utilisation thérapeutique d'une combinaison contenant un agoniste du récepteur de farnésoïde X et un conjugué à action prolongée triplement agoniste ou un triple agoniste, ou une combinaison contenant en outre un inhibiteur de l'acétyl-CoA carboxylase en plus des précédents.
PCT/KR2021/009210 2020-07-17 2021-07-16 Utilisation thérapeutique d'une combinaison contenant un conjugué à action prolongée triplement agoniste ou un triple agoniste Ceased WO2022015115A1 (fr)

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IL299841A IL299841A (en) 2020-07-17 2021-07-16 Therapeutic use of a combination containing a long-acting triple agonist or triple agonist conjugate
CA3186199A CA3186199A1 (fr) 2020-07-17 2021-07-16 Utilisation therapeutique d'une combinaison comprenant un conjugue a action prolongee triplement agoniste ou d'un agoniste triple
EP21841859.8A EP4183419A4 (fr) 2020-07-17 2021-07-16 Utilisation thérapeutique d'une combinaison contenant un conjugué à action prolongée triplement agoniste ou un triple agoniste
US18/016,145 US20230310630A1 (en) 2020-07-17 2021-07-16 Therapeutic use of combination comprising triple agonistic long-acting conjugate or triple agonist
CN202180062143.3A CN116209475A (zh) 2020-07-17 2021-07-16 包括三重激动长效缀合物或三重激动剂的组合的治疗用途
JP2023503210A JP2023535382A (ja) 2020-07-17 2021-07-16 三重作用性持続型結合体又は三重作用剤を含む組合せ物の治療学的用途
BR112023000585A BR112023000585A2 (pt) 2020-07-17 2021-07-16 Composição farmacêutica e uso da mesma
MX2023000699A MX2023000699A (es) 2020-07-17 2021-07-16 Uso terapéutico de combinación que comprende un conjugado de acción prolongada triple agonista o agonista triple.
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996032478A1 (fr) 1995-04-14 1996-10-17 Genentech, Inc. Polypeptides modifies a demi-vie accrue
WO1997034631A1 (fr) 1996-03-18 1997-09-25 Board Of Regents, The University Of Texas System Domaines analogues a l'immunoglobuline a demi-vies prolongees
WO2007021129A1 (fr) 2005-08-16 2007-02-22 Hanmi Pharmaceutical Co., Ltd. Procédé pour la production en masse d'une région fc d'immunoglobuline libre de résidus de méthionine initiale
KR20150023013A (ko) * 2012-06-21 2015-03-04 인디애나 유니버시티 리서치 앤드 테크놀로지 코퍼레이션 수용체 활성을 나타내는 글루카곤 유사체
WO2017116204A1 (fr) 2015-12-31 2017-07-06 한미약품 주식회사 Triple activateur activant le récepteur du glucagon, du glp-1 et du gip
JP2020516627A (ja) * 2017-04-12 2020-06-11 ギリアード サイエンシーズ， インコーポレイテッド 肝疾患を処置する方法

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2839867A1 (fr) * 2011-06-22 2012-12-27 Indiana University Research And Technology Corporation Co-agonistes du recepteur du glucagon et du recepteur du gpl-1
TWI767095B (zh) * 2017-12-21 2022-06-11 美商美國禮來大藥廠 腸促胰島素(incretin)類似物及其用途

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996032478A1 (fr) 1995-04-14 1996-10-17 Genentech, Inc. Polypeptides modifies a demi-vie accrue
WO1997034631A1 (fr) 1996-03-18 1997-09-25 Board Of Regents, The University Of Texas System Domaines analogues a l'immunoglobuline a demi-vies prolongees
WO2007021129A1 (fr) 2005-08-16 2007-02-22 Hanmi Pharmaceutical Co., Ltd. Procédé pour la production en masse d'une région fc d'immunoglobuline libre de résidus de méthionine initiale
KR20150023013A (ko) * 2012-06-21 2015-03-04 인디애나 유니버시티 리서치 앤드 테크놀로지 코퍼레이션 수용체 활성을 나타내는 글루카곤 유사체
WO2017116204A1 (fr) 2015-12-31 2017-07-06 한미약품 주식회사 Triple activateur activant le récepteur du glucagon, du glp-1 et du gip
WO2017116205A1 (fr) 2015-12-31 2017-07-06 한미약품 주식회사 Conjugué persistant d'un triple activateur activant le récepteur du glucagon, du glp-1 et du gip
KR20170080522A (ko) * 2015-12-31 2017-07-10 한미약품 주식회사 글루카곤, glp-1 및 gip 수용체 모두에 활성을 갖는 삼중 활성체의 지속형 결합체
JP2020516627A (ja) * 2017-04-12 2020-06-11 ギリアード サイエンシーズ， インコーポレイテッド 肝疾患を処置する方法

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
FUTURE MED CHEM., vol. 12, no. 6, March 2020 (2020-03-01), pages 533 - 561
G. J. WEBB ET AL., J. AUTOIMMUNITY, vol. 64, November 2015 (2015-11-01), pages 42 - 52
H. NEURATHR. L. HILL: "The Proteins", 1979, ACADEMIC PRESS
HEPATOLOGY, vol. 38, 2003, pages 1008 - 17
J CLIN INVEST., vol. 108, 2001, pages 1167 - 74
NORLIN JENNY, MIRANDA DIEGO A, BATES JAMIE G, ZOIS NORA E, VEIDAL SANNE, FEIGH MICHAEL, TREVASKIS JAMES L, LATTA MARKUS: "1810-P: Triple Combination Therapy of GLP-1 Receptor Agonist Semaglutide with an FXR Agonist and AC Inhibitor Reverses Nonalcoholic Steatohepatitis (NASH) in Diet-Induced and Biopsy-Confirmed Mice", DIABETES (NEW YORK, N.Y.), vol. 69, no. Supplement_1, 1 June 2020 (2020-06-01), US , XP009533268, ISSN: 0012-1797, DOI: 10.2337/db20-1810-P *
See also references of EP4183419A4
TREVASKIS JAMES L, NORLIN JENNY, MIRANDA DIEGO A, BATES JAMIE G, ZOIS NORA E, VEIDAL SANNE, FEIGH MICHAEL, LATTA MARKUS: "1813-P: Coadministration of a GLP-1/Glucagon receptor agonist with an FXR agonist and ACC inhibitor reverses nonalcoholic steatohepatitis (NASH) in diet-induced and biopsy-confirmed mice", DIABETES, vol. 69, no. Suppl. 1, 1 June 2020 (2020-06-01), US , XP009533267, ISSN: 0012-1797, DOI: 10.2337/db20-1813-P *

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